|Year : 2021 | Volume
| Issue : 2 | Page : 169-172
Neoadjuvant chemotherapy in cancer breast
Jiya Mulayamkuzhiyi Saju1, KG Krishnakumar2
1 Department of General Surgery, Government Medical College, Alappuzha, Kerala, India
2 Department of General Surgery, Government Medical College, Trivandrum, Kerala, India
|Date of Submission||19-Jun-2021|
|Date of Decision||05-Sep-2021|
|Date of Acceptance||06-Sep-2021|
|Date of Web Publication||15-Nov-2021|
Dr. Jiya Mulayamkuzhiyi Saju
Vattamala (H), Manarcadu P. O., Kottayam - 686 019, Kerala
Source of Support: None, Conflict of Interest: None
Introduction: This observational study attempts to assess the proportion of carcinoma breast patients showing complete pathological response to neoadjuvant chemotherapy post-surgery and to study the factors contributing to complete pathological response. Subjects and Methods: This was conducted on 290 female patients with locally advanced breast cancer who underwent neoadjuvant chemotherapy (NACT) followed by surgery in the Department of General Surgery from April 2018 to April 2020. The post-operative histopathological specimen was checked for evidence of pathological complete response (pCR). Statistical analysis was done using SPSS software. Results: The proportion of breast cancer patients with pCR following NACT was 18.6% (54 out of 290 patients). Factors found to have a significant association with pCR were the clinical size of tumour, size of lump in mammogram, histological grade of tumour and duration of swelling. Clinical stage, molecular subtype of cancer and age had no significant association with pCR. Conclusion: Less advanced tumours i.e., those with clinical and mammogram size ≤5 cm achieved higher pCR than more advanced tumours. Higher histological grade achieved less pCR than histological Grade I tumours. Association could not be elicited between pCR and triple-negative molecular subtype.
Keywords: Complete pathological response, locally advanced breast cancer, neoadjuvant chemotherapy, triple negative breast cancer
|How to cite this article:|
Saju JM, Krishnakumar K G. Neoadjuvant chemotherapy in cancer breast. Kerala Surg J 2021;27:169-72
| Introduction|| |
Locally advanced breast cancer (LABC), which is clinical Stage IIB and above, is treated with neoadjuvant chemotherapy (NACT) followed by surgery. Pathological complete response (pCR) is defined as the absence of residual neoplasm (either T0 or Tis) in the breast and axillary lymph nodes after NACT. Achievement of pCR in the modified radical mastectomy (MRM) or breast conservation surgery (BCS) specimen is deemed as a surrogate marker for long-term disease-free survival. pCR (ypT0-is/ypN0) can easily differentiate between patients with favourable and unfavourable outcomes in breast cancer. LABC is classified as per the staging system proposed by AJCC into stage IIB, IIIA, IIIB and IIIC, of which 25%–30% are inoperable.,
The objectives of this study were to assess the proportion of LABC patients showing complete pathological response to NACT as evaluated in the MRM/BCS specimen post-surgery and to study the clinicopathologic factors that may contribute to pCR. The association of pCR with factors such as age, duration of swelling, clinical size, clinical stage, histological grade, mammogram size of the breast lump and triple-negative molecular subtype are explored in this study.
| Subjects and Methods|| |
This is an observational study conducted for 2 years (April 2018 – April 2020) in the general surgery department of a tertiary care teaching hospital. Female patients with LABC who underwent NACT followed by MRM/BCS were included in the study. Patients with metastatic breast cancer and male patients with breast cancer were excluded from the study. Those patients who were unwilling to take part in the study and those who had incomplete clinical and histopathological records were excluded from the study. Thus, a total of 290 female patients with carcinoma breast were included in this study.
pCR in this study was defined as the eradication of the invasive disease in both breast and lymph nodes (T0/Tis and N0) as per the Chevallier classification. Patients who attained pCR and the factors contributing to pCR were studied. Ductal carcinoma in situ was considered part of pCR. The majority of the study population took anthracycline and taxane-based chemotherapy (Adriamycin-Cyclophosphamide + Docetaxel/Paclitaxel); number of cycles varying from 3 to 8.
Baseline tumour size was recorded clinically and by mammogram. Core needle biopsy report was collected to assess the ER, PR and HER2 status by immunohistochemistry. Equivocal HER2 status was re-examined by FISH (fluorescent in situ hybridization) to assess HER2 amplification. Tumours were classified into four molecular subtypes based on hormone receptor study. Axillary lymph node assessment was done clinically. Histological grade of the tumour was assessed from the histopathology report acquired postoperatively, graded as per the modified bloom Richards on (MBM) grading.
Association between pCR and the following factors was studied; age (≤50, 51–60, and >60), duration of symptoms (0–6 months, 7–12 months, 13–24 months, 25–36 months), clinical size (≤5, >5 cm) clinical stage (Stage IIB, IIIA, IIIB, IIIC), tumour grade (Grade I, II, III), mammogram size of tumour (≤2, 2.1–5, >5 cm) and molecular subtype (triple negative).
All data were analysed using the Statistical Package SPSS version 20.0. Chi-square test was used to find the association between clinicopathological variables and pCR. P < 0.05 was considered statistically significant.
| Results|| |
Pathological complete response obtained in this study
pCR was obtained in 54 out of 290 patients (18.6%) with a 95% confidence interval of 76.9–85.9.
Factors associated with pathological complete response
Age and pathological complete response
The mean age at diagnosis was 54.7 + 9.8 years. The majority of the study population belonged to 40–70 age group [Figure 1]. No statistically significant association was found between age and pCR (P = 0.449) as shown in [Table 1].
Duration of swelling and pathological complete response
The majority of the study population presented between 0 and 6 months of tumour onset [Table 2]. Statistically significant association was found between the duration of swelling and pCR (P = 0.023). Higher the duration of swelling, higher the pCR [Table 3].
|Table 2: Percentage distribution of sample according to duration of swelling|
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|Table 3: Association between duration of swelling and pathological complete response|
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Clinical size and pathological complete response
Majority (250/290 = 86.2%) had breast lump size more than 5 cm, followed by 35 (12.1%) with size 2.1–5 cm and 5 (1.7%) <2 cm. pCR was high for breast lump of size <5 cm (12/30 = 30%) compared to >5 cm (42/250 = 16.8%). This difference was statistically significant (P = 0.046). This shows that less advanced tumours showed higher pCR than more advanced tumours.
Clinical stage and pathological complete response
The majority of the study population fell into stage IIIB (49.7%, n = 144). Stage IIIB includes T4N0M0/T4N1M0/T4N2M0 as per the AJCC 8th edition. This was followed by stage IIIA (29.7%, n = 86), stage IIIC (12.4%, n = 36) and stage IIB (8.3%, n = 24). There is no significant association between clinical stage and pCR (P = 0.881) as detailed in [Table 4].
|Table 4: Comparison between clinical stage and pathological complete response|
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Histological grade and pathological complete response
The majority of the study population belonged to histological Grade II (63.8%, n = 185), followed by Grade III (31.7%, n = 92) and Grade I (4.5%, n = 13). The study observed a statistically significant association between histological grade and pCR (P = 0.021), as detailed in [Table 5]. As per this, grade I tumours showed maximum response to NACT compared to other grade tumours.
|Table 5: Association between histological grade and pathological complete response|
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Mammogram size of tumour and pathological complete response
Majority had breast lump of size 2.1–5 cm in mammogram (65.2%, n = 189), followed by >5 cm (30.7%, n = 89) and 0–2 cm (4.1%, n = 12). Mammogram size of the breast lump between 0 and 2 cm showed the highest pCR whereas a higher sized tumour in mammogram achieved less pCR [Table 6]. This association was statistically significant at P = 0.001 level. This clearly establishes that less advanced tumours showed higher pCR.
|Table 6: Association between size of lump in mammogram and pathological complete response|
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Molecular subtypes and pathological complete response
Of all the molecular subtypes, triple negative constituted 33.1% (n = 96) and HER2 positive constituted 13.4% (n = 39) and all others 53.5% (n = 155). About 24% (n = 23) of triple negative subtype showed pCR compared to 16% of other molecular subtypes. However, this was not statistically significant (P = 0.100).
| Discussion|| |
Breast cancer is now being considered a heterogenous disease because it encompasses molecular subtypes which vary in gene expression patterns and response to chemotherapy.
Not only can NACT assess the response of tumour to chemotherapy but also addresses micrometastatic disease. In a study done at the University of Texas M.D. Anderson Cancer Centre, where, out of 372 LABC patients who received NACT, 16% (n = 60) had a pCR in the primary tumour. pCR increases the likelihood of BCS, particularly in patients with large tumours.
In a study by Rouzier et al., breast tumour pCR was highly correlated with initial tumour size. Disease-free survival (DFS) was found to be significantly superior in patients with pCR in a large pooled analysis by von Minckwitz et al.
The proportion of complete pathological response got in this study is 18.6% (54 of 290 patients). This is similar to studies done by Díaz-Casas et al. wherein the overall rate of pCR was 15.2% (n = 63). In yet another study by Wang et al., pCR rate achieved was 12.2% in the young cohort and 13.4% in the old cohort. This signifies that the pCR rate obtained in the present study is similar to studies done in other parts of the world, irrespective of demographic differences.
In this study, higher pCR rate was found in tumours with clinical size <5 cm (P = 0.046). This result is similar to that obtained by Kuerer et al., which showed patients with less advanced primary tumours (stages T0 through T2) showed higher pCR (21%) compared to patients with stage T3 or T4 (7%). Mammogram size also correlates with pCR in that lesser the size of breast lump in mammogram, higher the pCR. This association was found to be significant at P = 0.001 level. This signifies that detection of tumours, when they are small in size, assures better survival for the patient if pCR is considered a marker for disease-free survival.
In this study, tumour onset of more than 6 months duration implied higher pCR. However, it is not clear of how this could be interpreted since duration, as reported by patients could vary on a large scale. Furthermore, tumours with histological grade I showed higher pCR than grade II and III tumours (P = 0.021). This is in contrary to studies by Kuerer et al., where patients with a pCR had initial tumours that were more likely to be anaplastic (P = 0.01).
In this study, age was not found to be associated with pCR (P = 0.449). This is similar to a study conducted by Prete et al., in Italy where age (P = 0.0730) did not seem to correlate with pathological response.
Although 24% (n = 23) of triple-negative patients were found to attain pCR compared to 16% (n = 31) of other molecular subtypes, the result did not attain statistical significance in this study (P = 0.100). This is in contrast to studies by Carey et al., where triple negative and HER2 positive subtypes displayed higher rates of pCR (27% and 36%, respectively) compared to luminal subtype (7%). Neither did the clinical stage of the tumour categorized as stage IIB, IIIA, IIIB, IIIC influence pCR to statistical significance (P = 0.811).
In short, the prognostic factors for pCR identified in this study were duration of swelling, clinical size of breast lump, histological grade and size of breast lump in mammogram. Age, clinical stage and triple-negative molecular subtype were not identified as factors influencing pCR in this study.
The relevance of this study is that, given the potential toxicity associated with chemotherapy, one could consider abbreviating adjuvant chemotherapy in patients who attain pCR in both breast and axilla after NAT. In Protocol B-18 of the National Surgical Adjuvant Breast and Bowel Project, patients who achieved a pCR had DFS and OS of 75% and 85%, respectively, compared with 58% and 73% for patients with residual disease. Thus, pCR can be used as a surrogate endpoint for assessing response to NACT.
Limitations of this study include the fact that it was conducted in a single institution and that a study on how recurrence rate is influenced by pCR was not done. It is a known fact that pCR does not completely eliminate disease recurrence. However, the findings of the study may serve as a hypothesis on which future research may be conducted regarding pCR and its projection of survival rate. Factors affecting pCR definitely help in predicting better outcomes in later life.
| Conclusion|| |
pCR in LABC patients who underwent NACT followed by surgery was found to be 18.6%. Factors affecting pCR were duration of swelling (P < 0.05), clinical size of breast lump (P < 0.05), histological grade of tumour (P < 0.05) and mammogram size of breast lump (P < 0.001). Less advanced and lower grade tumours showed higher pCR. Higher pCR was noted in tumour onset more than 6 months. Age, clinical stage and triple-negative subtype were not found to be associated with pCR (P > 0.05). This study could serve as a benchmark for future studies determining the possible recurrence rate and survival rate of breast cancer patients based on pCR. If one knows the factors which influence pCR, one could also predict the survival of a patient with advanced breast cancer based on these simple clinical and pathologic parameters.
- We thank Dr. Abdul Latheef, HOD, Dept of General Surgery, Govt Medical College, Trivandrum under whose guidance and support this study was conducted in the department
- We thank Dr Sulfekar M S, Additional Professor, Govt Medical College, Kollam, for his immense support
- We thank Dr Anusruthi Gopi, who suggested this topic
- We thank Dr Lekhasree and Dr Nithya Pankajakshan for statistical support.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6]