|Year : 2013 | Volume
| Issue : 2 | Page : 245-249
Pathological predictive factors for tumor response in locally advanced breast carcinomas treated with anthracyclin-based neoadjuvant chemotherapy
Trupti Patel, Anuja Gupta, Manoj Shah
Department of Pathology, Gujarat Cancer and Research Institute, M.P Shah Cancer Hospital, Ahmedabad, Gujarat, India
|Date of Web Publication||13-Jun-2013|
Room # 412, Department of Pathology, The Gujarat Cancer and Research Institute, NCH Campus, Asarwa, Ahmedabad - 380 016, Gujarat State
Source of Support: None, Conflict of Interest: None
Aim: Neoadjuvant chemotherapy (NACT) is used as a primary treatment for locally advanced breast carcinoma (LABC) and also extended to operable breast cancer. The aim of this study was to evaluate the predictive value of different histological parameters in core biopsy of LABC patients treated with anthracycline-based chemotherapy regimen. Pathological assessment of the excised tumor bed is the gold standard and is essential for identifying the group of patients with pathologic complete response (pCR) or pathologic noncomplete response (pNR).
Materials and Methods: A total of 50 patients with stage II and III breast carcinoma were included in the study. Pretreatment core biopsy histological features include tumor type, histological grade, presence of tumor necrosis, lymphovascular emboli (LVE) and immunohistochemical stains for estrogen receptor (ER) and progesterone receptor (PR) were obtained. Patients were given 3-6 cycles of NACT. Pathological response was assessed.
Result: Seven out of 50 patients achieved pCR. A total of 71.4% patients who achieved pCR had tumor necrosis on initial core biopsy while only 30% pNR cases had this feature (P =0.035). Breast carcinoma other than ductal type was chemoresistant. Of 47 core biopsies, LVE was observed in 13 cases (28 %) of which 11 showed axillary node metastasis. None of these 13 cases had pCR, thus having poor predictive value.
Conclusion: Pathological parameters like type of tumor, presence of LVE and tumor necrosis in the core biopsy can predict the response to NACT in routine stain. Tumor necrosis and type of breast carcinoma are predictive parameters for tumor responsiveness to NACT. LVE was reliable in predicting axillary lymph node metastasis.
Keywords: Breast core biopsy, histological parameters, neoadjuvant chemotherapy, tumor necrosis
|How to cite this article:|
Patel T, Gupta A, Shah M. Pathological predictive factors for tumor response in locally advanced breast carcinomas treated with anthracyclin-based neoadjuvant chemotherapy. J Can Res Ther 2013;9:245-9
|How to cite this URL:|
Patel T, Gupta A, Shah M. Pathological predictive factors for tumor response in locally advanced breast carcinomas treated with anthracyclin-based neoadjuvant chemotherapy. J Can Res Ther [serial online] 2013 [cited 2019 Sep 17];9:245-9. Available from: http://www.cancerjournal.net/text.asp?2013/9/2/245/113366
| > Introduction|| |
Neoadjuvant chemotherapy (NACT) is increasingly being used in the treatment of primary breast cancer, whose diagnosis is made by core biopsy, prior to surgical excision. Locally advanced breast carcinoma (LABC) accounts for 5-15% of newly diagnosed cases of breast cancer in the United States and up to 60% of new cases in developing countries.  Tumor response can be evaluated clinically by palpation or by breast imaging during therapy. However, this is a subjective measurement of assessing tumor response. Clinical and radiological assessment of response often underestimates or overestimates the amount of residual carcinoma present. Thus, pathological assessment of the excised tumor bed is the gold standard and is essential for identifying the group of patients with pathologic complete response (pCR) or pathologic noncomplete response (pNR).
Identification of biologic and pathologic properties that correlate with the ability of a tumor to respond to chemotherapy has the potential to improve patient care. Ineffective chemotherapy and its side effect can be avoided in patients that are not likely to respond to common chemotherapy regimens. Modified Scarff-Bloom-Richardson (mSBR) grade, various proliferation marker and some of the biological markers like estrogen receptor (ER), progesterone receptor (PR), Her-2/neu, p53 and Bcl-2 have been suggested as predictors of response to NACT. ,,, Recently, molecular profiling of tumors has been used to predict the response to certain chemotherapy regimen. , However, this technology is still not used for routine clinical use.
The main aim of this study was to evaluate histopathogical predictive markers in clinical and pathologic response of breast cancers treated with NACT. Core biopsy and post chemotherapy specimens were assessed in routine stain. Specimens were also assessed for different type of chemotherapy response at primary and metastatic site and residual cancer burden (RCB) was estimated by RCB system. 
| > Materials and Methods|| |
This is a retrospective study of 50 patients with LABC, who were treated in our hospital over a period of 1 year. We included the cases with clinical stage IIB, stage III (A and B) and inflammatory carcinoma of breast correspond to LABC as defined by American Joint Committee on Cancer (AJCC staging Manual, 6 th edition). Eligible patients for this study were patients with cancer in untreated stages II B, stage III A and B, and inflammatory carcinoma of breast cancer confirmed by core biopsy. Patients were in good general health with normal complete blood count and comprehensive metabolic profile.
Pretreatment core biopsy histological features including tumor type, presence of tumor necrosis, angiolymphatic emboli (lymphovascular emboli (LVE) and histological grade (mSBR grades 1-3) were recorded. Imunohistochemical stains for ER and PR was obtained on the core biopsy only. For ER staining we used ER antibody clone SP-1 (Thermo scientific, 1:100 dilution) and for PR antibody clone SP-2 (Thermo scientific, 1:100 dilution). Hormonal receptor status was considered as positive when more than 10% of neoplastic cells exhibited nuclear staining.
Patients were given anthracycline-based chemotherapy regimen with 5-fluorouracil, Adriamycin or epirubicin and cyclophosphamide (FAC/FEC) every 3 weeks during 3-6 cycles before surgery. Minimum of 3 cycles were given and it proceeded up to 6 cycles only if there was clinical response as well as no undue chemotoxicities. Post treatment specimens were observed for type and grade of tumor, LVE and chemotherapy response at primary and metastatic site. RCB was estimated by RCB system  according to the following variables.
The RCB index was found to be an improvement over currently used risk factors for the prediction of distant relapse after NACT. According to literature, if independently validated, it is suggested to provide an accurate surrogate endpoint for patient survival. Hence, according to score RCB I and II was given. Both of these cases showed response histologically, while RCBIII does not show any response.
- The largest two dimensions (in millimeters) of the residual tumor bed in the breast (largest tumor bed if multicentric disease).
- Histologic mapping of the entire largest cross-sectional area of the residual tumor bed.
- Histologic assessment of the percentage of the tumor bed area that contains carcinoma (all carcinoma, i.e., invasive and in situ), selected as one of 0%, 1%, 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90%.
- Histologic estimate of the percentage of the carcinoma in the tumor bed that is in situ, selected as one of 0%, 1%, 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90%.
- Number of positive (metastatic) lymph nodes.
- Largest diameter (in millimeters) of the largest nodal metastasis.
Thus, this system uses residual invasive carcinoma cellularity distributed over the tumor bed, the number of lymph nodes with metastasis, size of the largest metastasis and percentage of ductal carcinoma in situ (DCIS) combined mathematically according to formula available at http://www.mandersort.org/breastcancer_RCB.
RCB score was calculated and RCB index value categorized as one of four RCB classes.
RCB 0: Score 0 : PCR (No carcinoma in breast or lymph node).
RCB I: Score 1.36 : Partial response.
RCB II: Score 1.36-3.26 : Partial response.
RCB III: Score >3.26 : Chemoresistant.
The statistical analysis was done using SPSS software (Chicago, IL, USA) and to calculate the P value and the Chi-square test.
| > Results|| |
Patient's age ranged from 26 to 70 years, median range was 45.5 years. Out of 50 invasive carcinomas diagnosed on core biopsy, 44 cases were invasive duct carcinoma of which two cases turned out as inflammatory carcinoma, 1 invasive lobular carcinoma (ILC), 2 mixed type (lobular and ductal) and 3 were invasive carcinoma not further categorized for any histological parameters because of paucicellularity. [Table 1] demonstrates pathological characteristics of the tumor as determined by the core biopsy and mastectomy.
|Table 1: Pathological characteristics of the tumor as determined by the core biopsy and mastectomy specimen|
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Of 50 cases, mSBR grade was done in 46 cases of core biopsy, in which 36 cases (78%) were low grade (mSBR 1-2) and 10 cases (22%) were high grade (mSBR 3). In four cases mSBR was not estimated as one was lobular carcinoma and in three only few tumor cells were present. In post chemotherapy mastectomy specimen, 7 cases showed pCR while 43 cases were in pNR group. Low mSBR grade was seen in 34 of 41 (83%) and high grade in 7 of 41 cases (17%). In remaining two cases, one was pure ILC and in the other tumor was present only in lymph node so histological grade was not assessed. There was not much difference in mSBR grading in core biopsy and post chemotherapy mastectomy specimen. DCIS component was seen in 32 of 43 cases (74%) of mastectomy specimen varying from 1% to 40% of tumor bed along with invasive component. None of our core biopsy showed in situ component.
After NACT, morphological changes were evident in 42 of 50 cases (84%) at primary site, while 8 of 50 (16%) did not show any response means in chemoresistant group. Responses included fibroelastosis and hyalinized vascular stroma (85%), stromal edema (23%), necrosis, hemosiderin deposition with foamy histiocytes (13% each), lymphocytic infiltration (18%), calcification in 13%, cholesterol clefts and multinucleated giant cells in 5% each. Fibroelastosis and hyalinized vascular stroma, sheets and discretely lying foamy histiocytes were seen in all cases of pCR group. Nucleomegaly, cytomegaly, cytoplasmic/nuclear vacuolization, pleomorphic and bizarre nuclei were seen in majority of pNR cases. Cytotoxic effect was also seen in nonneoplastic breast parenchyma. Sixteen of 50 cases were axillary lymph node negative. Response in lymph nodes was seen as fibrosis with mucin pools (21%), aggregates or sheets of foamy cells (12%) with or without viable tumor cells.
Distribution of pathological response as calculated by the RCB system was as follows: RCB-0 (pCR) in 7 cases (14%), RCB-I in 1 case (2%), RCB-II in 15 cases (30%) and RCB-III in 27 cases (54%). Of these 27 cases of RCB-III, 19 cases showed minimal response while 8 cases did not show any response histologically. Out of these eight cases one was inflammatory carcinoma, one ILC, one ILC+IDC and remaining were ductal carcinoma. Seven among these eight cases (88%) were of low SBR grade. Five out of 7 patients (71.4%) who achieved pCR had tumor necrosis on initial core biopsy while 12 of 40 pNR cases (30%) had this feature. These showed a strong association between tumor necrosis in the core biopsy and pCR to NACT ( P =0.035). As shown in [Table 2], the presence of tumor necrosis in the core biopsy had a sensitivity of 71% and specificity of 70% in predicting pCR. Though, the positive predictive value was low (29%), the absence of tumor necrosis was highly predictive of pNR (negative predictive value 93%).
Of 47 core biopsies, LVE was observed in 13 cases (28%). As shown in [Table 3], sensitivity is low (35%) but it has a high specificity (88%) and positive predictive value (85%) to predict axillary node metastasis. None of these 13 cases achieved pCR, thus representing a poor prognostic parameter in core biopsy. However, the P value was not significant ( P =0.095).
|Table 3: Presence of LVE in core biopsy as a predictive factor for axillary lymph node metastasis|
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In our study, pathological complete response (pCR) in breast was seen in 7 cases (14%) as compared with lymph node where it was 1 in 34 cases (0.03%). Remaining 16 cases were lymph node negative. In pNR group, 65% (22/34 cases) of lymph nodes were chemoresistant while in breast only 16% (8/50 cases) were chemoresistant [Table 4]. This suggests heterogeneity of tumor at primary and metastatic site, thus, not showing similar response to chemotherapy at both sites.
We found no clear difference in ER and PR expression in the pCR and pNR group [Table 1] to NACT.
| > Discussion|| |
Breast cancer is the most frequent malignancy in women in the world. LABC remains a daily encounter and challenge for medical and surgical oncologists in developing countries. Even operable large tumors are also managed by primary systemic therapy or NACT. Incidence of breast cancer increases in early age group in India. 23.5% of women were younger than 35 years in our study too.
In this study, we evaluate the different histological parameters in core biopsy that can predict pCR to anthracyclin-based chemotherapy. We also describe the histomorphological changes that occur in post chemotherapy mastectomy specimens and calculate RCB.
Majority of breast carcinomas in our study are of ductal type. It is interesting to note that all of our complete responders were classified as ductal carcinoma, while lobular carcinoma and inflammatory carcinoma were in RCB-III group that is chemoresistant. Our finding is consistent with a published study showing invasive ductal carcinoma is more responsive to chemotherapy than lobular carcinoma and inflammatory carcinoma. ,, We did not demonstrate any association between high histologic grade (mSBR) and responsiveness to NACT, similar to the study by Pu et al.  But all our complete nonresponders demonstrated low mSBR grade. In many studies [12 ],,, SBR grade assessed from available pretreatment core biopsy correlated significantly with the type of pathological response. Tumors with high nuclear grade were more likely to achieve pCR compared with low nuclear grade.
Tumor necrosis in initial core biopsy emerged as a significant histological parameter in predicting tumor response to NACT ( P =0.035) in our study. Its significant association with pCR, its good specificity and sensitivity suggests that its presence or absence should be mentioned in the histopathology report. As shown in our study, LVE in core biopsy can be of value in predicting tumor response to this NACT. It is considered to be a poor prognostic factor as none of these cases had pCR, thus it is included in the report when assessing the histological parameters in a core biopsy. Though there are controversial results in the literature about LVE in core biopsy and axillary node metastasis and some investigations found that core biopsy assessment of LVE is not reliable.  We and others noticed that LVE in the core biopsy can be of clinical use to predict metastasis in the axillary nodes.  Even though core biopsy LVE was not sensitive (35%), it had a high specificity (88%) and a high positive predictive value (85%) in predicting axillary node metastasis.
We could not draw a definite correlation between ER/PR status and an excellent pathologic response as is evident in other studies but few authors have apparently been more successful to demonstrate greater response of NACT in receptor negative patients. ,,, There is a paucity of published data concerning the incidence and outcome of patients with a pCR in the primary tumor and axillary lymph nodes after NACT. Most of the literature on NACT concerning pCR rates refers to and reports on pCR in the primary tumor alone. Kuerer et al. did not find evidence of invasive tumor in the breast primary and axillary lymph nodes after NAC in 12% of their 372 patients with locally advanced breast cancer patients.  In our cohort 14% of the cases had complete pathological response (pCR). In contrast, Fisher et al.  found a 7% rate of pCR in the primary tumor and axillary lymph nodes in 185 patients with local operable breast cancer and clinically positive axillary lymph nodes. Miller and Payne in their study of 176 patients with large and locally advanced breast cancers, 14% were included in grade 5 which is characterized by absence of any tumor cell and presence of vascular fibroelastic stroma only. 
The clinical response to NACT does not always accurately reflect the pathologic response. There are different systems for evaluating pathologic response to treatment. We follow the RCB system to calculate RCB. We feel it is more comfortable as it is easily incorporated in routine diagnostic practice without adding to the cost of patient care. A stepwise guide for the pathologic evaluation along with illustration is provided on the internet free of charge. Each variable in the equation has prognostic significance. Symmans et al. reported that RCB measurement provides a continuous parameter of response, so that all subject responses contribute to the analysis. They note that patients with minimal RD (RCB-I) had the same 5-year prognosis as those with pCR and extensive RD (RCB-III) was associated with poor prognosis.  All patients with RCB-III after FAC chemotherapy without hormone therapy, suffered distant relapse within 3 years. Thus, RCB index is an independent risk factor that improves the prediction of distant relapse after NACT.
In summary, in the core biopsy presence of LVE, absence of tumor necrosis and lobular type breast carcinoma are poor histologic parameters to predict the tumor responsiveness to combined anthracyclin-based NACT. LVE was reliable in predicting axillary lymph node metastasis. Although our study of 50 patients is small, the results are promising to consider them as a part of routine core biopsy report. Still, these factors have to be confirmed in large prospective clinical trials.
| > References|| |
|1.||Esteva FJ, Hortobagyi GN. l0 ocally advanced breast cancer. Hematol Oncol Clin North Am 1999;13:457-72. |
|2.||Amat S, Penault-Llorca F, Cure H, Le Bouedëc G, Achard JL, Van Praagh I, et al. Scarff-Bloom-Richardson (SBR) grading: A pleiotropic marker of chemosensitivity in invasive ductal breast carcinomas treated by neoadjuvant chemotherapy. Int J Oncol 2002;20:791-6. |
|3.||Buchholz TA, Davis DW, McConkey DJ, Symmans WF, Valero V, Jhingran A, et al. Chemotherapy-induced apoptosis and Bcl-2 levels correlate with breast cancer response to chemotherapy. Cancer J 2003;9:33-41. |
|4.||Kandioler-Eckersberger D, Ludwig C, Rudas M, Kappel S, Janschek E, Wenzel C, et al. TP53 mutation and p53 overexpression for prediction of response to neoadjuvant treatment in breast cancer patients. Clin Cancer Res 2000;6:50-6. |
|5.||Faneyte IF, Schrama JG, Peterse JL, Remijnse PL, Rodenhuis S, van de Vijver MJ. Breast cancer response to neoadjuvant chemotherapy: Predictive markers and relation with outcome. Br J Cancer 2003;88:406-12. |
|6.||Buchholz TA, Stivers DN, Stec J, Ayers M, Clark E, Bolt A, et al. Global gene expression changes during neoadjuvant chemotherapy for human breast cancer. Cancer J 2002;8:461-8. |
|7.||Chang JC, Wooten EC, Tsimelzon A, Hilsenbeck SG, Gutierrez MC, Elledge R, et al. Gene expression profiling for the prediction of therapeutic response to docetaxel in patients with breast cancer. Lancet 2003;362:362-9. |
|8.||Symmans WF, Peintinger F, Hatzis C, Rajan R, Kuerer H, Valero V, et al. Measurement of residual breast cancer burden to predict survival after neoadjuvant chemotherapy. J Clin Oncol 2007;25:4414-22. |
|9.||Singh M, Capocelli KE, Marks JL, Schleicher RB, Finlayson CA, Seligman PA. Expression of vascular endothelial growth factor and proliferation marker MIB1 are influenced by neoadjuvant chemotherapy in locally advanced breast cancer. Appl Immunohistochem Mol Morphol 2005;13:147-56. |
|10.|| Pu RT, Schott AF, Sturtz DE, Griffith KA, Kleer CG. Pathologic features of breast cancer associated with complete response to neoadjuvant chemotherapy: Importance of tumor necrosis. Am J Surg Pathol 2005;29:354-8. |
|11.|| Cocquyt VF, Blondeel PN, Depypere HT, Praet MM, Schelfhout VR, Silva OE, et al. Different responses to preoperative chemotherapy for invasive lobular and invasive ductal breast carcinoma. Eur J Surg Oncol 2003;29:361-7. |
|12.||Alvarado-Cabrero I, Alderete-Vázquez G, Quintal-Ramírez M, Patiño M, Ruíz E. Incidence of pathologic complete response in women treated with preoperative chemotherapy for locally advanced breast cancer: Correlation of histology, hormone receptor status, Her2/Neu, and gross pathologic findings. Ann Diagn Pathol 2009;13:151-7. |
|13.||Bonadonna G, Veronesi U, Brambilla C, Ferrari L, Luini A, Greco M, et al. Primary chemotherapy to avoid mastectomy in tumors with diameters of three centimeters or more. J Natl Cancer Inst 1990;82:1539-45. |
|14.||Fisher ER, Wang J, Bryant J, Fisher B, Mamounas E, Wolmark N. Pathobiology of preoperative chemotherapy: Findings from the National Surgical Adjuvant Breast and Bowel (NSABP) protocol B-18. Cancer 2002;95:681-95. |
|15.||Gharbi O, Trabelsi A, Chafai R, Zayen A, Ezzair F, Hochlef M, et al. Clinical and pathological response to neoadjuvant anthracycline based chemotherapy in women with breast cancer. World J Oncol 2010;1:167-72. |
|16.||Sharifi S, Peterson MK, Baum JK, Raza S, Schnitt SJ. Assessment of pathologic prognostic factors in breast core needle biopsies. Mod Pathol 1999;12:941-5. |
|17.||Davis DW, Buchholz TA, Hess KR, Sahin AA, Valero V, McConkey DJ. Automated quantification of apoptosis after neoadjuvant chemotherapy for breast cancer: Early assessment predicts clinical response. Clin Cancer Res 2003;9:955-60. |
|18.||Kuerer HM, Newman LA, Smith TL, Ames FC, Hunt KK, Dhingra K, et al. Clinical course of breast cancer patients with complete pathologic primary tumor and axillary lymph node response to doxorubicin-based neoadjuvant chemotherapy. J Clin Oncol 1999;17:460-9. |
|19.||Ogston KN, Miller ID, Payne S, Hutcheon AW, Sarkar TK, Smith I, et al. A new histological grading system to assess response of breast cancers to primary chemotherapy: Prognostic significance and survival. Breast 2003;12:320-7. |
[Table 1], [Table 2], [Table 3], [Table 4]
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