|Ahead of print publication
A study on clinico-pathological assessment of response to neoadjuvant chemotherapy in breast carcinoma
Manisha Mohapatra1, Yerraguntla Subramanya Sarma2
1 Department of Pathology, GSL Medical College and General Hospital, Rajahmundry, Andhra Pradesh, India
2 Department of Medical Oncology, GSL Medical College and General Hospital, Rajahmundry, Andhra Pradesh, India
|Date of Submission||17-Jun-2019|
|Date of Decision||22-Nov-2019|
|Date of Acceptance||19-Dec-2019|
|Date of Web Publication||03-Oct-2020|
Department of Pathology, GSL Medical College and General Hospital, NH-16, Lakshmipuram, Rajahmundry - 533 296, Andhra Pradesh
Source of Support: None, Conflict of Interest: None
Context: Neoadjuvant chemotherapy (NACT) has become a strategy in the multidisciplinary treatment approach to breast cancer. Since clinical and radiological responses do not correlate well with residual tumor after treatment, pathological evaluation of tumor response to chemotherapy is essential for accurate assessment.
Aims: The aim of this study is to assess clinicopathological response to NACT in patients with invasive breast carcinoma.
Settings and Design: Single institution, retrospective study was conducted for 4 years.
Subjects and Methods: The study included 95 cases with the clinical diagnosis of locally advanced breast cancer and invasive breast carcinoma on histopathological examination of core needle biopsy/lumpectomy specimen. These cases were assessed for estrogen, progesterone, and human epidermal growth factor receptor 2 (HER2) receptors and treated with four cycles of NACT (adriamycin-cyclophosphamide) therapy. Histopathological examination of postchemo modified radical mastectomy specimens was performed following standard protocol. The pathological response of tumor to chemotherapy was assessed on Miller-Payne grading (MPG) and residual disease in breast and lymph node (RDBN) level.
Statistical Analysis Used: Data were analyzed in percentages and presented in charts and tables.
Results: Histopathological examination of pre-chemo biopsy specimens revealed invasive ductal carcinoma No special type (NST) in maximum, 89 (93.7%) cases. Majority 43 (45.3%) cases were HER2-positive followed by estrogen receptor-positive and/or progesterone receptor positive and HER2-positive type seen in 23 (24.2%) cases and 22 (23.1%) cases were triple negative. Sixteen (16.8%) and 76 (80%) cases showed pathological complete response (pCR) and partial pathological response, respectively, to NACT on MPG; 12 (12.6%) and 83 (87.4%) cases showed pCR and residual disease, respectively, on RDBN level. Majority 37.5% and 50% of cases showing pCR on MPG and RDBN level, respectively, were triple negative.
Conclusions: This study highlights the clinicopathological response to NACT in carcinoma breast patients and identifies the molecular subtypes of these patients likely to respond to NACT.
Keywords: Breast carcinoma, Miller-Payne grade, neoadjuvant chemotherapy, pathological response, residual disease in breast and lymph node level
| > Introduction|| |
Neoadjuvant chemotherapy (NACT) refers to primary or preoperative therapy to treat patients with systemic agents before the definitive surgical removal of carcinoma. It was introduced several decades ago in 1973 to downstage the locally advanced breast cancer (LABC). Initially, it was used as a method of local control of these high-risk cases by transforming inoperable tumors into tumors amenable to resection; subsequently was extended to operable early-stage breast cancer mainly to improve the eligibility for breast-conserving surgery among women presenting with bulky tumor.,, Now, NACT has become a strategy in the multidisciplinary treatment approach to breast cancer. NACT also allows an in vivo assessment of tumor chemosensitivity. Several studies suggest that patients with any form of LABC achieve high response rate after induction chemotherapy and the complete clinical and pathological response of primary breast cancer has been shown to have great prognostic value., Since clinical and radiological responses to NACT do not correlate well with residual breast cancer after treatment, pathologic evaluation of tumor response to chemotherapy is essential for accurate assessment. This study was undertaken in our institute to assess the clinico-pathological response to NACT in patients with invasive breast carcinoma.
| > Subjects and Methods|| |
This is a retrospective observational study, which included a total number of 95 cases over a period of 4 years (January 2013–December 2016) with the clinical diagnosis of LABC and invasive breast carcinoma on histopathological examination of core needle biopsy/lumpectomy specimen. All of these cases were assessed for estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2) receptor status. Ki67% and fluorescent in situ hybridization could not be performed due to a lack of resources. Immunohistochemistry was performed for ER (clone 1D5), PR (Clone PR88) and HER2 (clone CB11) supplied from BioGenex (USA). ER and PR status was assessed by the Allred scoring system. The cut off value of ER and PR was defined as >1% of tumor cells with nuclear staining., Immunohistochemical staining for HER2 was scored according to the standard criteria as 0, 1+, 2+, or 3+. Score 3+ was considered to be HER2-positive. Basing on the ER, PR, and HER2 receptor status these cases were classified into five molecular subtypes such (i) ER-positive, PR-positive, and HER2-negative (ER +ve, PR +ve, and HER −ve), (ii) ER-positive, PR-negative, and HER2-negative (ER +ve, PR −ve, and HER2–ve), (iii) ER-positive and/or PR positive and HER2-positive (ER +ve and/or PR +ve and HER2 +ve), (iv) ER-negative, PR-negative, and HER2-positive (ER −ve, PR −ve, HER2 +ve, i.e., HER2 +ve), (v) ER-negative, PR-negative and HER2-negative (ER −ve, PR −ve, HER2 −ve, i.e., triple negative)., All of these cases had been treated with four cycles of adriamycin and cyclophosphamide (AC) chemotherapy. Histopathological examination of postchemo modified radical mastectomy (MRM) specimens was performed on formalin-fixed paraffin block sections stained with Hematoxylin and Eosin. There are various methods of assessing the pathological response of tumor to chemotherapy. Pathological complete response (pCR) is defined as the absence of tumor in the breast and lymph node. Our assessment was based on Miller-Payne grading (MPG) criteria and residual disease in the breast and lymph node (RDBN) level. MPG assesses the pathological response by comparing the tumor cellularity of core biopsy (before treatment) with resected tumor in breast (after treatment) and comprises five grades where Grade I is considered to be pathological no response (pNR), Grade II, III, and IV are categorized as partial pathological responses (pPRs). Grade V is the absence of invasive tumor cells in post-NACT breast is considered as pCR. RDBN is calculated using the formula for RDBN index criteria into four levels: RDBN1 is considered to be pCR; RDBN2, RDBN3, and RDBN4 are considered as pathological partial responses which show residual disease in three different amounts.
Following MRM, all of these cases were treated with adjuvant therapy of four courses of taxol, radiotherapy as per the standard protocol and hormone receptor-positive cases received additional endocrine therapy. Since all of these cases were freely treated under “Arogyasri scheme,” anti-HER2 treatment could be given to affordable HER2-positive cases but not routinely.
| > Results|| |
Preneoadjuvant chemotherapy clinico-pathological findings
[Table 1] depicts the pre-NACT clinico-pathological assessment findings of all the studied 95 cases. The age of these cases ranged from 27 to 75 years with the mean age of 49.3 years. There were 52 (54.7%) cases in premenopausal age and 43 (45.3%) cases in postmenopausal age. All of these cases were LABC belonging to the American Joint Committee on Cancer (AJCC) clinical stage IIIB. The average size of breast tumor was found to be 6.5 cm with maximum number, 64 (67.0%) cases showed tumor of >5.0 cm. In 75.0% (71/95) cases, there was axillary lymphadenopathy. Histopathological examination of core needle biopsies (n = 91) and lumpectomy specimens (open diagnostic biopsy, n = 4) revealed invasive ductal carcinoma NST in majority, 89 (93.7%) cases followed by invasive papillary carcinoma, 3 (3.3%) cases, 1 (1.0%) case belonged to each in invasive lobular carcinoma, mucinous and medullary carcinoma variant. Basing on ER, PR, and HER2 receptor status, maximum number of cases were observed to be HER2-positive cases as seen in 43 (45.3%) cases, followed by ER-positive and/or PR-positive with HER2-positive type seen in 23 (24.2%) cases, triple negative type, 22 (23.1%) cases and 7 (7.4%) cases were ER-positive, PR-positive and HER2-negative. None of these cases was found to be ER-positive, PR-negative, and HER2-negative.
|Table 1: Preneoadjuvant chemotherapy clinico-pathological assessment result|
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Postneoadjuvant chemotherapy histopathological assessment
[Figure 1] illustrates the post-NACT histopathological findings MRM specimens (n = 95). The average size of the residual tumor in breast on gross examination was found to be 3.7 cm. Thirteen (14.0%) cases had no residual tumor. Of the 82 cases with residual tumor, majority, 53 (56.0.0%) had tumor of size 2.0–5.0 cm followed by 18 (19.0%) cases with tumor of >5.0 cm and in 11 (11.0%) cases the tumor was of <2.0 cm. Eighty-eight (92.6%) cases did not show any of the margins to be involved by the tumor, whereas 7 (7.4%) cases showed margin involvement. Fifty-one, 54.0% of these 95 cases showed positive lymph nodes; maximum number, 26 (51.0%) cases had N1 Stage followed by N2 Stage in 19 (37.0%) cases.
While assessing the pathological response of breast cancer to NACT based on MPG [Figure 1], it was observed that 16 (16.8%) of total 95 cases belonged to MPG-V who did not show any residual invasive cancer or showed occasional foci of ductal carcinoma in situ in breast thus considered as pCR and 3 (3.2%) cases belonged to MPG-I (pNR) by showing very minimal or no loss of tumor following NACT. Seventy-six (80%) of 95 cases showed pPR, which consisted of 48 (50.5%), 25 (26.3%), and 3 (3.2%) cases in MPG-II, III, and IV, respectively. The pathological response to NACT based on the RDBN level is discerned in [Figure 1]. It was evident that 12 (12.6%) of total of 95 cases belonged to RDBN level 1 who did not show either residual tumor in breast or lymph node thus considered as pCR. Eighty-three (87.4%) cases showed residual disease (pPR) in response to NACT, of which 35 (36.8%), 27 (28.4%), and 21 (22.4%) cases belonged to RDBN level 2, 3, and 4 respectively. Four (25%) of the 16 cases showing pCR on MPG had positive lymph nodes. Hence, the discrepancy of pCR based on MPG criteria and RDBN level was due to residual nodal disease. [Figure 2] shows the histopathological findings of MPG–V (pCR) and MPG–I (pNR) and [Figure 3] shows the findings of MPG-II and III (pPR). Post-NACT pathological assessment revealed downstaging of AJCC stage in the majority of cases. Of the 76 cases who showed pPR as per MPG, 50 (65.8%) and 26 (34.2%) cases belonged to AJCC Stages II and III, respectively; the three cases with pNR had AJCC Stage II. Similarly, it was found that of the 83 cases showing residual disease as per the RDBN level, 57 (68.7%) and 26 (31.3%) cases belonged to AJCC Stages II and III, respectively.
|Figure 2: Miller–Payne Grade V (pathological complete response) and Grade I (pathological no response). (a and d) Preneoadjuvant chemotherapy trucut breast biopsies showing cellular invasive ductal carcinoma NST (H and E, ×100).(b and c) postneoadjuvant chemotherapy modified radical mastectomy specimen showing pathological complete response gross and microscopically; (e and f) Postneoadjuvant chemotherapy modified radical mastectomy specimen showing pathological no response gross and microscopically (H and E, ×100)|
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|Figure 3: Miller–Payne Grade II and III (partial pathological response). (a and d) preneoadjuvant chemotherapy breast biopsies showing cellular invasive ductal carcinoma NST microscopically (H and E, ×100) (b and c) postneoadjuvant chemotherapy modified radical mastectomy specimen showing partial pathological response (Miller-Payne Grading-II) gross and microscopically (H and E, ×100). (e and f) Postneoadjuvant chemotherapy modified radical mastectomy specimen showing partial pathological response (Miller-Payne Grading-III) gross and microscopically (H and E, ×100)|
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[Table 2] depicts the association of pathological response to NACT based on MPG with molecular subtypes. It was observed that among the 16 cases who showed pCR based on MPG, majority, 6 (37.5%) were triple-negative breast cancers (TNBCs) followed by 5 (31.25%) cases of HER2-positive type. Maximum number, 38 (50.0%) of the 76 cases who showed pPR were HER2 positive followed by ER-positive and/or PR positive and HER2-positive type and triple-negative type attributing to 16 (21.05%) cases each. The three cases with pNR to NACT were ER-positive and/or PR positive and HER2-positive type. [Table 3] discerns the association of pathological response to NACT based on the RDBN level with molecular subtypes. It was observed that the maximum number, 6 (50%) of 12 cases who showed pCR to NACT were triple-negative followed by 4 (33.4%) cases of HER2-positive type. The 83 cases who showed pPR comprised maximum number 39 (47.0%) cases of HER2-positive type followed by 22 (26.5%) cases of ER-positive and/or PR positive and HER2-positive type and 16 (19.3%) cases of triple-negative type.
|Table 2: Association of pathological response to neoadjuvant chemotherapy based on Miller-Payne grading with molecular subtypes|
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|Table 3: Association of pathological response to neoadjuvant chemotherapy based on residual disease in breast and lymph node level with molecular subtypes|
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| > Discussion|| |
The rationale behind the increased use of NACT in breast cancer is its several advantages. Apart from downstaging the tumor or rendering the tumor surgically resectable it helps in faster evaluation of likely benefits of the new approaches to treatment as well as gives an insight into the biological characteristics of individual tumor. Patients with invasive carcinoma of the breast have a significant risk of harboring occult micrometastatic disease in the distant organs as by the time cancer is palpable, it is already advanced and has potential for distant micrometastases. NACT allows earlier exposure of these micrometastases to chemotherapeutic agents. Since the prognosis of the patient depends on the response of cancer to NACT, it is highly essential to assess the tumor response accurately following the routine courses of NACT. A tumor that shows complete clinical response shows residual carcinoma on microscopic examination, conversely a palpable residual mass shows only fibrosis without residual carcinoma on the microscopic examination. Hence, pathological assessment of tumor response to chemotherapy remains the gold standard of assessment.
Preneoadjuvant chemotherapy clinico-pathological findings
The study comprised 95 cases with an age range of 27–75 years and the mean age of presentation being 49.3 years. Earlier study conducted by us also showed the mean age of cancer breast patients to be 48.7 years. Parmar et al. from Tata memorial hospital, Mumbai and Vasudevan et al. from Kerala in their study observed the mean age of cancer breast patients to be 47.6 and 50.2 years, respectively., We observed the mean clinical tumor size to be 6.5 cm (T3) before the administration of NACT which is similar to Parmar et al. observing mean tumor size to be 7.4 cm (T3) but larger as compared to observations made by Corben et al. from Boston and Vasudevan et al. who found the mean clinical size of pre-NACT tumor to be 4.3 and 3.75 cm (T2), respectively.,
Further, it was observed that majority, 67.0% of our cases had pre-NACT tumor of >5.0 cm which is similar to study conducted by Iqbal et al. from Ryadh  who observed tumor size of >5.0 cm in 77.0% (36/54) of cases. Seventy-one, 75.0% of these 95 cases had axillary lymphadenpathy which is similar to Iqbal et al., Zhao et al. and Parmar et al. who found axillary lymphadenopathy in 70.0%, 85.2% and 67.5% of their studied cases.,, All of our cases belonged to AJCC clinical stage IIIB which differs from Iqbal et al. who observed AJCC clinical stage III in 59.0% (32/54) cases. Invasive ductal carcinoma NST was the most common type observed microscopically as seen in 93.7% cases which is concordant to the observations made by various other authors and also our previous study.,, Basing on ER, PR, and HER2 receptor status, we observed maximum number to be belonging to HER2-positive subtype as seen in 43 (45.3%) cases followed by ER-positive and/or PR-positive and HER2-positive type, 23 (24.2%) cases, triple negative seen in 22 (23.1%) cases. ER- and PR-positive with HER2 negative type were encountered in the lowest number of cases as seen in 7 (7.4%) cases. These findings differ from the study conducted by others where majority of cases are ER-positive, PR positive, and HER2-negative type.,, The high percentage of HER2 positive cases in our study may be attributed to the advanced stage, higher grade (Nottingham histologic grade–II) of the disease and lower age group as majority (23/43, 53.5%) of these patients are in premenopausal age.
Postneoadjuvant chemotherapy histopathological assessment
Following four cycles of AC therapy, the gross pathological examination of MRM specimens revealed the average size of the residual tumor to be 3.7 cm which showed a 43.0% reduction of primary tumor size. Corben et al. and Parmar et al. observed the mean pathological tumor size to be 1.8 and 4.1 cm in the post-NACT MRM specimens which showed 53.0% and 44.6% reduction of primary tumor, respectively., We observed 13 (14.0%) cases without any residual tumor on gross pathological examination and majority, 53 (56.0%) cases had tumor of size <5.0 cm which is similar to Zhao et al. who also observed residual tumor of <5.0 cm in 56.8% of their studied cases.
Fifty-one (54.0%) of cases showed positive lymph nodes which is at par with Corben et al. observing positive lymph nodes in 53.0% of studied cases but varies from Parmar et al. and Zhao et al. who observed positive lymph nodes in 67.0% of their studied cases. Thus, the reduction in tumor size and lymph node status after NACT corroborated with the study conducted by various authors.,, Waldrep et al. from the USA in a study of 84 carcinoma breast patients treated with NACT did not observe any correlation between distant disease-free survival (DDFS) or overall survival (OS) with pre-NACT tumor size measured by magnetic resonance imaging and post-NACT tumor size examined pathologically. He noted that more positive lymph node involvement after receiving NACT leads to worse outcome. On microscopic examination of MRM specimens, we observed the margin involvement in 7 (7.2%) cases. There is a paucity of literature on margin involvement in the post-NACT MRM specimens, only stray document by Iqbal et al. depicts the margin involvement in 1 (3.1%) of the studied 40 cases.
Basing on the MPG, We observed pCR in 16 (16.8%) out of 95 cases and majority, 76 (80.0%) of our cases showed pPR which was also similar to Zhao et al. who observed pCR and pPR in 12 (13.7%) and 67 (76.1%) cases, respectively. Various authors have ascribed that pCR to NACT occurs in 10%–20% cases. However, Corben et al. observed pCR in 5 (9.0%) of their studied 88 cases. In a study from Kerala, Mukherjee et al. observed pCR basing on MPG criteria in 12 (23.1%) of 52 cases. Our observation of 3.2% cases with pNR differs from Zhao et al. and Mukherjee et al. who found pNR in 16.2% (9/88) and 11.5% (6/52) of their studied cases, respectively. Basing on the RDBN level, we observed the pCR in 12 (12.6%) cases and residual disease (pPR) in 83 (87.4%) of total 95 cases which correlated well with Zhao et al. who observed pCR in 11.4% (10/88) and residual disease in 88.6% (78/88) cases. It has been observed that patients showing pCR to NACT have favorable outcome and are associated with significantly better OS and DDFS as compared to those with partial or no response to NACT.,,, Waldrep et al. concluded from their study that the higher the RDBN level, the higher is the distant relapse and death rate and decreased DDFS as well as OS due to disease. They also found that cases with pNR and pPR as per the MPG criteria also showed decreased DDFS and OS. Sun et al. observed that patients with good response to NACT did not show any difference in local and regional recurrence. However, we could not study this aspect due to the limitation of our study to clinic pathological assessment of NACT in breast cancer patients.
While associating the pathological response to NACT with molecular subtypes, we observed that majority of patients showing pCR based on MPG and RDBN level were triple negative as seen in 37.5% (6/16) cases and 50.0% (6/12) cases, respectively. These findings corroborated well with the observations of Kulka et al., Liedtke et al. and Zhao et al. who also observed maximum number of their cases with pCR belonging to TNBC subtype.,, Ring et al. stated that patients with ER-negative tumor are likely to achieve a better pCR to NACT than ER-positive tumor. However, Corben et al. and Carey et al. observed pCR in majority of their HER2-positive cases., Although, TNBCs are associated with increased risk for visceral metastasis, recurrence and death rate, those patients who achieve pCR have excellent survival. However, patients with TNBC showing residual disease following NACT have significantly worse survival as compared to non-TNBCs. It has also been observed that survival following NACT correlates with pathological response than receptor status of breast cancer.
Receptor status of breast cancer does not correlate with pathological response in patients who did not achieve pCR.
Following MRM, all of these cases were treated with four courses of taxol, radiotherapy, and hormone receptor positive cases were treated with additional endocrine therapy. Only those cases belonging to HER2 positive who could afford were treated with anti-HER2 therapy. Till the last course of treatment, all of these cases were asymptomatic.
| > Conclusions|| |
The study gave an insight into clinico-pathological response to NACT and the association of chemosensitivity with molecular subtypes of breast cancer patients in our hospital setting. It also endorsed the claim of various researchers stating that preoperative chemotherapy results in less morbid surgical treatment by downstaging the primary breast tumor and axillary metastases.
The authors are thankful to Dr. S. R. Nayak, Professor of Surgery and histopathology technicians of the Department of Pathology of GSL Medical College and General Hospital, Rajahmahendravaram for help and support.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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