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 Table of Contents  
ORIGINAL ARTICLE
Year : 2022  |  Volume : 13  |  Issue : 2  |  Page : 54-59

Clinicopathological factors predictive of pathological response and impact on disease-free survival in breast cancer: Analysis from a tertiary cancer centre in South India


Department of Radiation Oncology, Government Medical College, Kozhikode, Kerala, India

Date of Submission01-Dec-2021
Date of Acceptance01-Feb-2022
Date of Web Publication28-Feb-2022

Correspondence Address:
Dr. Vishnu Asokan
Department of Radiation Oncology, Government Medical College, Kozhikode, Kerala
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jrcr.jrcr_54_21

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  Abstract 


Aim: Neoadjuvant chemotherapy in carcinoma breast results in tumour downstaging and provides the opportunity to modify treatment based on response. Pathological complete response (pCR) is considered predictive of favourable long-term outcomes. The objective was to identify clinicopathological factors associated with pCR in breast cancer and disease-free survival (DFS). Subjects and Methods: Clinicopathological details of 106 breast cancer patients receiving neoadjuvant therapy were retrospectively analyzed. The statistical analyses were performed using the Chi-square test by SPSS software (version 18.0). Pvalues were considered statistically significant when <0.05. Results: The median age of the patients was 53 years. The overall pCR rate was 23.6%. From univariate analysis, a significant rate of pCR was detected in tumours with high grade or high Ki-67 scores (P = 0.001, P = 0.019), respectively. 29 patients relapsed of which 21 were distant metastasis. On Kaplan–Meier method analysis, statistically significant factors associated with decreased DFS were high Ki 67 and lymphovascular invasion positivity. Distant metastasis occurred in 4 patients with pCR and 19 patients without pCR. The 5-year DFS rate was 84% versus 69% in patients with pCR and without pCR, respectively. Conclusion: A higher rate of pCR was obtained with neoadjuvant therapy in tumours with high grade or Ki-67. Longer DFS is achieved by obtaining pCR with ideal neoadjuvant selection.

Keywords: Carcinoma breast, disease-free survival, neoadjuvant therapy, pathological complete response


How to cite this article:
Paramban MP, Asokan V, Tintu M V, Ajayakumar T. Clinicopathological factors predictive of pathological response and impact on disease-free survival in breast cancer: Analysis from a tertiary cancer centre in South India. J Radiat Cancer Res 2022;13:54-9

How to cite this URL:
Paramban MP, Asokan V, Tintu M V, Ajayakumar T. Clinicopathological factors predictive of pathological response and impact on disease-free survival in breast cancer: Analysis from a tertiary cancer centre in South India. J Radiat Cancer Res [serial online] 2022 [cited 2022 Aug 16];13:54-9. Available from: https://www.journalrcr.org/text.asp?2022/13/2/54/338801




  Introduction Top


Breast cancer is the most common cancer seen in women according to GLOBOCAN 2020.[1] Management of breast cancer is a multidisciplinary team approach with close cooperation between the surgeon, medical oncologist and radiation oncologist and pathologist.

Breast cancer is increasingly recognised as a heterogeneous disease and it encompasses a variety of entities with distinct morphological appearances and clinical behaviours. There is a strong correlation between the histology, the stage and the course of the disease. In recent years, it has become evident that this diversity is the result of genetic alterations.[2]

Human breast tumours are diverse in their natural history and their response to treatments. Therefore, tumour factors that can predict prognosis and response to specific therapies are of great potential benefit for the tailored treatment of invasive breast cancer.[3] It is a standard approach to administer adjuvant chemotherapy and/or hormonal treatment to reduce the risk for metastasis according to the histological, pathological and immunohistochemical staining characteristics of the tumour.

Neoadjuvant chemotherapy (NAC) refers to the administration of systemic therapy before surgical removal of a breast tumour. It results in downsising and downstaging of the tumour so that breast conservation surgery is feasible and thus improves cosmetic outcomes.[4] Another advantage is that therapeutic efficacy can be directly observed.[5] It also provides the opportunity to modify the treatment strategies based on the response.[6] The complete remission of all viable tumour tissues in the histopathologic examination of the removed breast and axillary tissue is referred to as pathological complete response (pCR).[7] As shown in the CTNeoBC pooled analysis, pCR is considered as a predictor of favourable long-term outcomes.[8]

There is a need for better therapies, and the neoadjuvant trial design could potentially serve as an efficient method for rapid triage and escalation/de-escalation of therapies to improve outcomes for young women with breast cancer.[9] pCR is also essential for determining the need for additional adjuvant therapy. Among patients with HER2-positive early breast cancer who had the residual invasive disease after completion of neoadjuvant therapy, the risk of recurrence of invasive breast cancer or death was 50% lower with adjuvant T-DM1 than with trastuzumab alone.[10] After standard NAC containing anthracycline, taxane or both, the addition of adjuvant capecitabine therapy was safe and effective in prolonging disease-free survival (DFS) and overall survival among patients with Triple-Negative Breast Cancer (TNBC) who had residual invasive disease on pathological testing.[11]

Targeted agents can also be used along with NAC.[12] On July 26, 2021, the FDA approved pembrolizumab as part of neoadjuvant treatment for high-risk TNBC. Studies have demonstrated positive patient-level associations between pCR and long-term outcome, including event-free survival and overall survival (OS) in the overall breast cancer population and among different breast cancer subtypes.[13] Clinical practice puts forth challenges of identifying optimal patients for neoadjuvant therapy, measuring response after NAC and optimal regimens.

The present study aimed to identify clinical and pathological factors associated with achieving pCR in breast cancer patients receiving NAC at our institution and to assess DFS. This will guide clinical decisions regarding the optimal use of NAC.


  Subjects and Methods Top


Ethics

“The authors assert that all procedures contributing to this work comply with the ethical standards of the relevant national guidelines on human experimentation and with the Helsinki Declaration of 1975, as revised in 2008, and have been approved by the Institutional Ethics Committee.

Study design

We retrospectively collected details of 106 breast cancer patients treated with neoadjuvant therapy at our institution from the hospital case records. Patients with distant metastasis or receiving neoadjuvant hormone therapy were excluded.

Study variables included age, menopausal status, histology, tumour(T) stage, lymph node status, tumour grade, hormonal receptor status, HER-2 status, Ki 67, lymphovascular invasion (LVI), type of chemotherapy and pathological response.

Initial biopsy specimen of all patients was used to confirm invasive carcinoma. Oestrogen receptor (ER), progesterone receptor (PR) and HER-2 receptor status were assessed either on the diagnostic core biopsy. Hormonal receptor status was considered positive if more than one per cent of tumour cells were stained for ER and/or PR. Tumours were considered HER2 positive if they were 3+ by immunohistochemistry or demonstrated gene amplification by in situ hybridisation. The grade was defined as the highest grade seen on any biopsy.

Clinical staging was determined based on the American Joint Committee on Cancer TNM Staging Manual, 8th edition. Tumour size was recorded before treatment and was defined as the largest dimension on any imaging modality before any treatment. The nodal disease was assessed by physical examination and/or radiological imaging, with or without a cytologic diagnosis. CECT thorax with abdomen and bone scan was done to rule out distant metastasis.

Neoadjuvant therapy consists of the following chemotherapeutic regimens: 3 cycles of FEC (Fluorouracil (5FU), Epirubicin, Cyclophosphamide) or 4 cycles of AC (Adriamycin, Cyclophosphamide) followed by 12 cycles of weekly Paclitaxel or 4 cycles of Docetaxel. In the case, of HER2-positive breast cancer, Trastuzumab was given in addition to chemotherapy and continued until 1 year after the start.

After the completion of neoadjuvant therapy, all patients underwent breast and axillary surgery, and the specimen was sent for a histopathology examination. A pCR was defined as having no residual invasive tumour in the breast and axilla surgical specimen. Patients who had only ductal carcinoma in situ (DCIS) in the breast tissue following neoadjuvant therapy were considered to have a pCR.

Patient follow-up details were collected and 5-year DFS was analyzed. Distant failure was diagnosed clinically, radiographically and/or pathologically.

Statistical analysis

The statistical analyses were performed using the Chi-square test by SPSS software (version 18.0). P-values were considered statistically significant when <0.05.


  Results Top


Patient characteristics

The median age of the patients was 53 years (range: 29–75 years). 61 (57.5%) were more than 50 years age. 50 (47.2%) were premenopausal and 56 (52.8%) were postmenopausal women. Most patients had invasive ductal carcinoma (97%). T3 (36.8%) and T4 (55.7%) tumours were the most common. Lymph node involvement N2 was present in around 39% of the patients. Hormone positive, HER2-negative tumours were 38% of the patients. 37 and 28 patients were triple negative and HER2 positive, respectively. High proliferating tumours, expressed by Ki-67 >30%, were about 35%. All patients received Doxorubicin, cyclophosphamide chemotherapy. Among the 37 triple-negative breast cancer patients, 8 received weekly paclitaxel following AC [Table 1].
Table 1: Characteristics of the study population

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Relationship between pathological response and clinicopathological data

After NAC, 25 patients (23.6%) achieved pCR, whereas 81 (76.4%) had residual disease. Out of 37 TNBC, 11 got pCR. Among 28 Her 2+, 8 attained pCR. 29 patients had breast only residual tumour, while 6 had residual disease in the axilla only. 43.4% had a residual tumour in both breast and axilla. 3 patients progressed on chemotherapy [Table 2].
Table 2: Comparative analysis of clinicopathological variables and pathology response

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When the relationship between pCR and clinicopathological data was analyzed statistically, no significant association was found among age, menopausal status, tumour and nodal stage, histology, LVI, oestrogen or PR positivity, Her 2 positivity, chemotherapy regimens. A higher rate of pCR was detected in the presence of a high-grade tumour, high Ki-67 score (P = 0.001, P = 0.019), respectively.

Survival

On Kaplan–Meier analysis, statistically significant factors associated with decreased DFS were tumours with high Ki-67 and the presence of LVI. Other factors contributing to decreased survival were a pathological residual tumour, TNBC or Her 2 neu-positive tumours [Figure 1]. Furthermore, those patients with residual tumours in both breast and axilla were having poor DFS [Figure 2]. For all patients, the overall distant recurrence rate was 19.8%. Distant metastasis occurred in 4 patients with pCR and 19 patients without pCR. The 5-year DFS was 84% versus 69% in patients with pCR and without pCR, respectively. The mean DFS was 46.2 months.
Figure 1: Survival curve disease-free survival and pathological complete response

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Figure 2: Survival curve disease-free survival and residual tumour

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Among the 25 patients who experienced pCR, none had an LRR (locoregional relapse). Among the 81 patients with residual disease after NAC, 8 developed LRR. Among the 8 Her 2 neu-positive patients who attained pCR, only one developed metastasis while 8 out of 20 with residual tumour had metastasis. Out of the 11 pCR attained TNBC patients, 2 developed metastasis. Among the 26 TNBC patients with residual tumour, 12 developed metastasis.

Relationship between clinicopathological data and relapse

Patient follow-up details were analyzed. 29 patients had a relapse of which 21 were distant metastasis and 6 were locoregional. 2 patients had both locoregional and distant metastasis [Table 3].
Table 3: Comparative analysis of clinicopathological variables and relapse

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  Discussion Top


In our study, we aimed to investigate the factors affecting pCR in carcinoma breast patients and found that a high Ki-67 score and the presence of a high-grade tumour were independent risk factors affecting pCR.

In the study by Cortazar and Geyer, pCR was lower with neoadjuvant therapy in patients with low-grade tumours. However, this group had more hormone receptor, positive patients.[14] In the study of Jarzab et al., tumour grade, Ki-67 and ER and PR negativity were determined as pCR-related tumour parameters.[15] The highest chance of pCR was observed in patients with high-grade tumours and Ki-67 ≥20%.

In the study of Spring et al., it was reported that higher pCR rates were observed in patients with grade 3 tumours.[13] Cortazar et al. analyzed 12 studies on neoadjuvant therapy and found that HER2-positive patient group had higher pCR than those with hormone receptor-negative.[8] In the study of Fayanju et al. although a higher pCR was shown in hormone receptor-negative patients, the hormone receptor status was not statistically significant other than survival.[16]

In the study of Silva et al., patients with high Ki-67 had a better response to NAC and a higher rate of clinical complete response.[17] To identify appropriate candidates for treatment intensification, our study provides practical foundational work for further risk stratification in patients treated with trimodality therapy. Given that these factors are readily available in surgical pathology reports and are predictive in patients without pCR, these findings are clinically relevant and applicable in the care of patients after NAC.

In recent years, the focus has been on minimising axillary surgery with an aim to reduce surgical morbidity.[18] In that study, they observed that 97.7% of cN0 breast cancer patients who achieved breast pCR had ypN0. This implies that the risk of missing patients with axillary lymph node metastases in these selected patients is highly unlikely. Identifying breast pCR may guide deescalating axillary treatment in selected patients. Future clinical trials should investigate if the omission of axillary surgery in these selected patients is safe when image-guided tissue sampling identifies breast pCR after NAC.

Patients who exhibit pCR have improved long-term outcomes with DFS compared with those who have residual disease.[19] However, it has not been proven that increasing pCR rates with more active regimens improve OS. The lymph node status after NAC is still the most important prognostic marker.

Regardless of the implications for survival, several groups have shown that the presence of LVSI predicts the development of distant metastatic disease.[20] The challenge remains to identify new treatment paradigms for the 60%–70% of patients who do not experience pCR after NAC. Although improvements in adjuvant therapy, such as Capecitabine, have improved outcomes in TNBC patients, those with TNBC still have an inferior OS and DFS compared with their non-TNBC counterparts.[11]

Next-generation sequencing and RNA expression analysis have identified targetable alterations, with agents currently under investigation in patients who do not experience pCR after NAC according to a sampling of the residual chemoresistant portion of the tumour.[21] Targeting of the pathways in the residual tumour persistent after NAC may also treat micrometastatic disease ultimately responsible for distant metastasis because these pathways would be derived from this pool of persistent chemoresistant tumour cells.


  Conclusion Top


Our study found that a higher rate of pCR was obtained with neoadjuvant therapy in high-grade tumours breast cancer or high Ki-67. Longer DFS can be achieved by obtaining pCR with ideal neoadjuvant therapy in selected patient groups. LVI and high Ki-67 were associated with poor DFS. The study also puts forth the hypothesis that smaller tumours with high grade and ki-67 status may benefit from NAC rather than upfront surgery.

Although the reduced number of patients and the retrospective analysis limited the value of this study, the data reported reflect the clinical practice of a single institution and suggest evaluating clinicopathological factors in patients with inoperable BC treated with NAC to predict the pathological response. Despite the increased knowledge of distinctive clinical and pathological parameters and insights into genetic variability of BC, a standardised model predictive of response to NAC is not presently available. A tailored evaluation of presumptive better chemotherapeutic regimens for each tumour subtype is desirable in the next future.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 2021;71:209-49.  Back to cited text no. 1
    
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Lüönd F, Tiede S, Christofori G. Breast cancer as an example of tumour heterogeneity and tumour cell plasticity during malignant progression. Br J Cancer 2021;125:164-75.  Back to cited text no. 2
    
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The Rise of Tailored Therapies in Breast Cancer. Available from: https://www.aacc.org/cln/cln-daily/2019/the-rise-of-tailored-therapies-in-breast-cancer. [Last accessed on 2021 Dec 03].  Back to cited text no. 3
    
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Kaufmann M, Hortobagyi GN, Goldhirsch A, Scholl S, Makris A, Valagussa P, et al. Recommendations from an international expert panel on the use of neoadjuvant (primary) systemic treatment of operable breast cancer: An update. J Clin Oncol 2006;24:1940-9.  Back to cited text no. 4
    
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von Minckwitz G, Raab G, Caputo A, Schütte M, Hilfrich J, Blohmer JU, et al. Doxorubicin with cyclophosphamide followed by docetaxel every 21 days compared with doxorubicin and docetaxel every 14 days as preoperative treatment in operable breast cancer: The GEPARDUO study of the German Breast Group. J Clin Oncol 2005;23:2676-85.  Back to cited text no. 5
    
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Untch M, Konecny GE, Paepke S, von Minckwitz G. Current and future role of neoadjuvant therapy for breast cancer. Breast 2014;23:526-37.  Back to cited text no. 6
    
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Wolmark N, Wang J, Mamounas E, Bryant J, Fisher B. Preoperative chemotherapy in patients with operable breast cancer: Nine-year results from National Surgical Adjuvant Breast and Bowel Project B-18. J Natl Cancer Inst Monogr 2001;2001:96-102.  Back to cited text no. 7
    
8.
Cortazar P, Zhang L, Untch M, Mehta K, Costantino JP, Wolmark N, et al. Pathological complete response and long-term clinical benefit in breast cancer: The CTNeoBC pooled analysis. Lancet 2014;384:164-72.  Back to cited text no. 8
    
9.
Spring L, Greenup R, Niemierko A, Schapira L, Haddad S, Jimenez R, et al. Pathologic complete response after neoadjuvant chemotherapy and long-term outcomes among young women with breast cancer. J Natl Compr Canc Netw 2017;15:1216-23.  Back to cited text no. 9
    
10.
von Minckwitz G, Huang CS, Mano MS, Loibl S, Mamounas EP, Untch M, et al. Trastuzumab emtansine for residual invasive HER2-positive breast cancer. N Engl J Med 2019;380:617-28.  Back to cited text no. 10
    
11.
Masuda N, Lee SJ, Ohtani S, Im YH, Lee ES, Yokota I, et al. Adjuvant capecitabine for breast cancer after preoperative chemotherapy. N Engl J Med 2017;376:2147-59.  Back to cited text no. 11
    
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Masoud V, Pagès G. Targeted therapies in breast cancer: New challenges to fight against resistance. World J Clin Oncol 2017;8:120-34.  Back to cited text no. 12
    
13.
Spring LM, Fell G, Arfe A, Sharma C, Greenup R, Reynolds KL, et al. Pathologic complete response after neoadjuvant chemotherapy and impact on breast cancer recurrence and survival: A comprehensive meta-analysis. Clin Cancer Res 2020;26:2838-48.  Back to cited text no. 13
    
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Cortazar P, Geyer CE Jr. Pathological complete response in neoadjuvant treatment of breast cancer. Ann Surg Oncol 2015;22:1441-6.  Back to cited text no. 14
    
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Jarząb M, Stobiecka E, Badora-Rybicka A, Chmielik E, Kowalska M, Bal W, et al. Association of breast cancer grade with response to neoadjuvant chemotherapy assessed postoperatively. Pol J Pathol 2019;70:91-9.  Back to cited text no. 15
    
16.
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.  Back to cited text no. 16
    
17.
Silva LR, Vargas RF, Shinzato JY, Derchain SF, Ramalho S, Zeferino LC. Association of menopausal status, expression of progesterone receptor and Ki67 to the clinical response to neoadjuvant chemotherapy in luminal breast cancer. Rev Bras Ginecol Obstet 2019;41:710-7.  Back to cited text no. 17
    
18.
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19.
Chen Y, Shi XE, Tian JH, Yang XJ, Wang YF, Yang KH. Survival benefit of neoadjuvant chemotherapy for resectable breast cancer: A meta-analysis. Medicine (Baltimore) 2018;97:e10634.  Back to cited text no. 19
    
20.
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21.
Balko JM, Giltnane JM, Wang K, Schwarz LJ, Young CD, Cook RS, et al. Molecular profiling of the residual disease of triple-negative breast cancers after neoadjuvant chemotherapy identifies actionable therapeutic targets. Cancer Discov 2014;4:232-45.  Back to cited text no. 21
    


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    Tables

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