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Discordance in early breast cancer for tumour grade, Estrogen Receptor, Progesteron Receptors and Human Epidermal Receptor-2 status between core needle biopsy and surgical excisional primary tumour
The Breast 20 (2011) 284e287
Contents lists available at ScienceDirect
The Breast journal homepage: www.elsevier.com/brst
Original article
Discordance in early breast cancer for tumour grade, Estrogen Receptor, Progesteron Receptors and Human Epidermal Receptor-2 status between core needle biopsy and surgical excisional primary tumour Veronique Lorgis a, Marie Paule Algros c, Cristian Villanueva a, Loic Chaigneau a, Antoine Thierryvuillemin a, Thierry Nguyen a, Martin Demarchi a, Fernando Bazan a, Jean Loup Sautiere b, Yolande Maisonnette-Lescot b, Frederic Ringenbach c, Patrick Bontemps d, Xavier Pivot a, e, * a
University Hospital Jean Minjoz, Department of Medical Oncology, 25030 Besançon Cedex, France University Hospital Jean Minjoz, Department of Surgery, 25030 Besançon Cedex, France c University Hospital Jean Minjoz, Department of pathology, 25030 Besançon Cedex, France d University Hospital Jean Minjoz, Department of radiotherapy, 25030 Besançon Cedex, France e Institut National de la Santé et de la Recherche Médicale, Unit 645, 25000 Besançon, France b
a r t i c l e i n f o
a b s t r a c t
Article history: Received 17 May 2010 Received in revised form 20 November 2010 Accepted 23 December 2010
The aim of the present study was to compare the tumour grade, Estrogen Receptor (ER), Progesteron Receptor (PgR) and Human Epidermal Receptor-2 (HER-2) status in the core needle biopsy (CNB) with those observed in the subsequent excisional primary tumour (EPT). All patients diagnosed with an early breast cancer in our University Hospital Center between January 1, 2005 and December 31, 2006 were included but exclusion criteria of patients with large tumour requiring neoadjuvant chemotherapy and cases with more than one tumour (multicentricity/multifocality tumours). Histological tumour grade assessed according to Nottingham Grading System (SBRm), ER, Pgr and HER-2 tumoural status were assessed twice in CNB and in EPT. A total of 175 patients were assessed. The concordance between CNB and EPT for Grade, ER, PgR and HER2 status were 75.4% (p > 0.00001), 84% (p > 0.00002), 78.3% (p ¼ 0.002) and 98.3% (p ¼ 0.486) respectively. In conclusion CNB can be used with confidence for HER2 determination. For grade, PgR and ER due to substantial discordance results from CNB should be used with caution. Ó 2011 Elsevier Ltd. All rights reserved.
Keywords: Breast cancer Human epidermal receptor- 2 Estrogen receptor Progesteron receptor Tumoral prognostic and predictive factors
Introduction Prognostic and predictive factors such patient’s age, tumour size, axillary nodal involvement, histological tumour grade, Estrogen Receptor (ER), Progesteron Receptor (PgR) and Human Epidermal Receptor-2 (HER-2) tumoural status are critical in the decision making process for the determination of the need and the types of adjuvant treatments. It seems of interest to identify where those parameters would be accurately assessed. Taking into account that Core needle biopsy (CNB) has become a wellestablished diagnostic tool for both palpable and non-palpable
* Corresponding author. University Hospital Jean Minjoz, Department of Medical Oncology, 25030 Besançon Cedex, France. Tel.: þ33 3 8166 86 93; fax: þ33 3 8166 88 08. E-mail address: [email protected] (X. Pivot). 0960-9776/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved. doi:10.1016/j.breast.2010.12.007
breast cancers.1,2 An assessment on the CNB might provide an early determination of those prognostic and predictive factors allowing an early organisation of the subsequent adjuvant treatments. Nevertheless, a CNB may not accurately assess the histological tumour grade, ER, PgR and HER-2 tumoural status. Results from several studies have shown a wide variability in terms of concordance between CNB sample and excisional primary tumour (EPT) assessment.3e12 Concordances are ranged from 61% to 99% for ER, PgR and HER-2 status. Rare reports were focused on grade concordance despite its impact on the therapeutic decision.10,11,13 The aim of the present study was to compare the tumour grade, ER, PgR and HER-2 status in the CNB with those observed in the subsequent tumorectomy. The impact in terms of adjuvant therapy proposal was assessed prospectively during a multidisciplinary concertation meeting.
V. Lorgis et al. / The Breast 20 (2011) 284e287
Patients and methods Patients selection and methods All patients diagnosed with an early breast cancer in our university Hospital center between January 1, 2005 and December 31, 2006 were included. All patients with large tumour requiring neoadjuvant chemotherapy were excluded to avoid any changes on tumours characteristics due to treatment. All patients with multicentricity/multifocality tumours were excluded. The histological primary tumoral size, and axillary nodal involvement were assessed in the surgery samples. Histological tumour grade assessed according to Nottingham Grading System (SBRm), ER, Pgr and HER-2 tumoural status were assessed in CNB and in EPT. The fixation processing used formalin 4% and a superimposable method for both assessment in CNB and ETP. The major difference was the duration of fixation. From 12 to 24 h and 24 to 48 h for CNB and ETP specimens, respectively. ER and Pgr were determined by immuno histo chemistry (IHC) using Novocastra clone 6F11 antibody at dilution 1/20 and Dako clone PgR636 antibody at dilution 1/30 for ER and PgR, respectively. Those staining were assessed by Benchmarkt XT Ventana using i vieuwÔ DAB (Ventana). Results are expressed in terms of percent of stained tumoral cells with a cutoff for positivity higher than 10%. HER-2 assessment was scored from 0 to 3þ. HER-2 determination was done by IHC with Dako polyclonal C-erbB-2 oncoprotein antibody at dilution 1/1000 with a Benchmarkt XT Ventana using kit i vieuwÔ DAB (Ventana). In case of overexpression scored at 2þ, FISH (PathVysion; vysis) was performed to determine the amplification if the ratio of HER2 gene signal to chromosome 17 signal was >2. The grading, ER, PgR and HER2 status were performed by two pathologists and in case of disagreement the case were reassessed by discussion A multidisciplinary concertation meeting was organised to determine the adjuvant treatment based on the following parameters: patient’s age, histological tumoral size, axillary nodal involvement, histological tumour grade, ER, PgR and HER2 status. The determination of adjuvant treatment was done twice for each patient with histological grade, ER, PgR and HER2 status determined from CNB or from EPT. Those adjuvant treatment proposal were performed randomly and the origin of the determination was blinded. The multidisciplinary concertation meeting included 4 medical oncologists, two pathologists, one radiotherapist and two surgeons.
285
The main disease characteristics including tumour sizes, TNM, axillary nodal involvement, histological types were reported in Table 1. Moreover the histological tumour grade, ER, PR and HER2 status assessed in CNB and in EPT were described in Tables 1 and 2. It was notable that a higher proportion of tumours were diagnosed as grade III in EPT than in CNB (4% versus 20%, respectively; p < 0.0001). The large majority of difference was linked to mitoses assessment, they were scored three in 4 versus 28 cases in CNB and EPT, respectively. A concordance rate of 75.4% was observed for grade determination between CNB and EPT. Of interest among the 92 tumours treated by neoadjuvant chemotherapy 24 were grade III (26%). ER was scored positive in 159 in the CNB (90.9%) versus 139 in the EPT (79.4%) (p ¼ 0.002). There was concordance between ER assessment in 84% of cases with discrepancy in 20 tumours. In 16 cases the assessment in EPT was found ER negative whereas the evaluation in CNB was positive. For PgR in the CNB, 142 (81.1%) were scored positive compared with 106 (60.6%) in the EPT (p < 0.00001). The concordance rate for PgR was 78.3%. In all cases the assessment in EPT was found ER negative whereas the evaluation in CNB was positive but one. HER2 was overexpressed in 12 tumours (7%) according to the assessment in CNB. Of interest, among the 92 tumours treated by neoadjuvant chemotherapy, 21 were HER2 positive (22.8%). No significant discrepancy was observed (p > 0.05). Nevertheless 3 variations were observed: 2 tumours HER2 positive in CNB were found to be HER2 negative in EPT and 1 tumour HER2 negative in CNB switch to positivity in EPT. The concordance rate was 98.3%. A multidisciplinary concertation meeting based on CNB or EPT analysis resulted on a 16.5% divergence rate for adjuvant treatments. In the subset of patients without nodal involvement, the variation rates reached 32%. Interestingly, among the 28 discrepant cases for RE, patients were treated by hormonotherapy in 22 cases. Discussion CNB is widely accepted in routine assessment for the diagnosis of breast cancer. It is a reliable method for histological diagnosis and it provides enough material to allow determination for additional markers such ER, PgR and HER2 status. Those analyses are critical due to their implications in the guidance of clinical adjuvant proposal. However it may be a concern if assessment in CNB could be less reliable than in EPT due to smaller size, heterogeneous
Table 1 Patients & tumours characteristics.
Statistical plan A descriptive analysis of the population was performed. Comparisons between tumour grades, ER, Pgr and HER2 status assessed in CNB and in EPT were done using Chi2 test. Adjuvant decision stated during the multidisciplinary concertation meeting was compared using a Chi2 test considering the origin of the assessment. Results Ninety-two patients were excluded due to a neoadjuvant strategy, 31 patients because the core needle biopsy found only in situ carcinoma, 3 cases because the excisional primary tumours showed only in situ carcinoma, and 3 and 10 cases because the primary tumour or the core needle biopsy didn’t allow IHC due to sample size, respectively. A total of 175 patients were assessed. The patients and treatment characteristics were summarised in Table 1.
Patients & tumour characteristics N ¼ 175 Median age (range) Histological subtype Nodal involvement Tumour size
RE þ RE PgR þ PgR HER2 þ HER2 Grade I Grade II Grade III Unknown
61 years (31e91) Ductal carcinoma Lobular carcinoma þ T1 T2 T3
157 18 95 80 118 50 7
(90%) (10%) (54%) (42%) (67.4%) (28.6%) (4%)
Core needle biopsy
Excisional primary tumour
P
159 16 142 33 11 164 40 123 7 5
139 36 106 69 10 165 50 85 35 5
P ¼ 0.002 P > 0.00002 P ¼ 0.486 P > 0.00001
286
V. Lorgis et al. / The Breast 20 (2011) 284e287
Table 2 Concordance between Core needle biopsy (CNB) and Excisional Primary Tumour (EPT) for tumour grade, ER, PgR and HER2 status.
Table 3 Recommendation for assessment of ER, PgR, HER2, tumour grade. Core needle biopsy
EPT/CNB þ Total
12 4 16
þ 24 135 159
Total 36 139
þ Total
32 1 33
35 105 142
69 106
þ Total
163 1 164
2 9 11
165 10
ER
HER2
ER
PgR PgR
HER2 Grade (SBRm)
Grade (SBRm) I II III Total
40 0 0 40
10 85 28 123
0 0 7 7
50 85 35
tumour status. This present study is one of the larger published series assessing Grade, ER, PgR and HER2 status in CNB and in EPT in the same group of patients. A good concordance was found between CNB and EPT for ER status with a tendency of a higher ER positive determination in CNB.12 Similarly, a trend for upscoring in CNB compared with EPT has been commonly reported by previous studies. The trend for PgR to be distributed more heterogeneously within the tumour might explain the higher discrepancy observed for PgR between CNB and EPT in our study.14 Similarly, previous studies suggest that the concordance rate between CNB and EPT is higher for ER than for PgR. In this present study the only difference between the analysis of CNB and EPT was related to the duration of fixation with the formalin 4%. Is this variable duration induced this discrepancy? HER2 assessment concordance was reported to be high between core and surgical specimen. Nevertheless, the evaluation could be altered in case of crush or retraction artefacts. Taking into account this point, the American Society of Clinical Oncology pointed out that CNBs with edge or retraction artefact involving the entire core should not be used as sample to interpret HER2.15 The same recommendation might be extended to the assessment of all markers detected by IHC. Surprisingly, the rate of tumours which overexpressed HER2 appeared to be lower in the present study than previous report. In primary breast cancer the rate of HER2 positive tumour is dramatically inferior than the rate of 20% reported in metastatic setting. In the Franche Comte Region (France) an independent assessment of HER2 status in primary tumour established that 10.6% of cases present an overexpressed HER2 status. Discrepancy with the present study might be explained by the non-inclusion of patients treated by neoadjuvant chemotherapy where the tumour’s HER2 positivity incidence was 22.8%. The small number of HER2 positive cases in the studied cohort might be insufficient to allow judgement to be made of assessment on core biopsy Interestingly the underscore in terms of grade III identification in CNB versus EPT appeared to be significant. This could be explained by the smaller sample size analysed in CNB versus EPT. This result suggest that grade determination need to be performed in the EPT. This discrepancy would be of substantial importance since it would imply a major change in adjuvant treatments. Thus, the variabilities in term of adjuvant treatment proposal were 16.5% and reached 32% among the subset of patient without axillary nodal involvement. The impact of the grade, ER, PgR and HER2 status discordance need to be taken into account.
Excisional primary tumour
Yes Yes Excluding CNBs with edge or retraction artefact involving the entire core Yes Yes Taking into account an upscoring in 16% of cases for CNB versus EPT Yes Yes Taking into account an upscoring in 22% of cases for CNB versus EPT Yes Yes Diagnosis of grade III in CNB is valuable, in other cases a re-assessment on EPT was required
In conclusion, one needs to take into account those discrepancies and to establish recommendations aimed to increase the accuracy for the determination of those prognostic or predictive factors. One can state that HER2 status could be perform either on CNB or on EPT. The recommendation of the American Society of Clinical Oncology excluding CNBs with edge or retraction artefact involving the entire core should being the rule. For PgR and ER due to substantial discordance results from CNB should be used with caution. One can consider reasonable to recommend a systematic second assessment of ER, PgR status. Grade criteria might always been determined on the EPT but a grade III is identified on the CNB. Those recommendations are listed in Table 3. The interest of an early determination of those prognostics and predictive parameters on the CNB is altered by discrepancies. This point suggests caution in interpretation of those results to state for the need of adjuvant treatment. Conflict of interest Xavier Pivot perceived Honorarium from Roche SA, Glaxo SmithKline and Novartis. Cristian Vilanueva perceived honorarium from Amgen and Sanofi Aventis. Loic Chaigneau, and Thierry Nguyen perceived honorarium from Sanofi Aventis. There is however no conflict of interest in regard to the content of this contribution. References 1. Benson SR, Harrison NJ, Lengyel J, Deacon C, Isgar B. Combined image guidance excision of non-palpable breast lesions. Breast 2004;13:110e4. 2. Verkooijen HM, Peeters PH, Pijnappel RM, Koot VC, Schipper ME, Borel Rinkes IH. Diagnostic accuracy of needle-localized open breast biopsy for impalpable breast disease. Br J Surg 2000;87:344e7. 3. 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;184:322e4. 4. Sutela A, Vanninen R, Sudah M, Berg M, Kiviniemi V, Rummukainen J, et al. Surgical specimen can be replaced by core samples in assessment of ER, PR and HER-2 for invasive breast cancer. Acta Oncol 2008;47:38e46. 5. Taucher S, Rudas M, Mader RM, Gnant M, Dubsky P, Roka S, et al. Prognostic markers in breast cancer: the reliability of HER2/neu status in core needle biopsy of 325 patients with primary breast cancer. Wien Klin Wochenschr 2004;116:26e31. 6. Gotzinger P, Gebhard B, Gnant M, Rudas M, Reiner A, Jakesz R. [Value of punch biopsy in diagnosis of palpable breast tumors. A prospective analysis of 150 patients]. Chirurg 1998;69:1068e71. 7. Hodi Z, Chakrabarti J, Lee AH, Ronan JE, Elston CW, Cheung KL, et al. The reliability of assessment of oestrogen receptor expression on needle core biopsy specimens of invasive carcinomas of the breast. J Clin Pathol 2007;60:299e302. 8. Harris K, Morafa I, Thomas V, Mokbel K. Core biopsy is accurate in determining the hormone receptor status of early breast cancer. Am J Surg 2004;187:568. author reply 568. 9. Cavaliere A, Sidoni A, Scheibel M, Bellezza G, Brachelente G, Vitali R, et al. Biopathologic profile of breast cancer core biopsy: is it always a valid method? Cancer Lett 2005;218:117e21.
V. Lorgis et al. / The Breast 20 (2011) 284e287 10. Burge CN, Chang HR, Apple SK. Do the histologic features and results of breast cancer biomarker studies differ between core biopsy and surgical excision specimens? Breast 2006;15:167e72. 11. Badoual C, Maruani A, Ghorra C, Lebas P, Avigdor S, Michenet P. Pathological prognostic factors of invasive breast carcinoma in ultrasound-guided large core biopsies-correlation with subsequent surgical excisions. Breast 2005; 14:22e7. 12. Arnedos M, Nerurkar A, Osin P, A'Hern R, Smith IE, Dowsett M. Discordance between core needle biopsy (CNB) and excisional biopsy (EB) for estrogen receptor (ER), progesterone receptor (PgR) and HER2 status in early breast cancer (EBC). Ann Oncol 2009;20:1948e52.
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13. Park SY, Kim KS, Lee TG, Park SS, Kim SM, Han W, et al. The accuracy of preoperative core biopsy in determining histologic grade, hormone receptors, and human epidermal growth factor receptor 2 status in invasive breast cancer. Am J Surg 2009;197:266e9. 14. Zidan A, Christie Brown JS, Peston D, Shousha S. Oestrogen and progesterone receptor assessment in core biopsy specimens of breast carcinoma. J Clin Pathol 1997;50:27e9. 15. Wolff AC, Hammond ME, Schwartz JN, Hagerty KL, Allred DC, Cote RJ, et al. American Society of Clinical Oncology/College of American Pathologists guideline recommendations for human epidermal growth factor receptor 2 testing in breast cancer. Arch Pathol Lab Med 2007;131:18e43.
Contents lists available at ScienceDirect
The Breast journal homepage: www.elsevier.com/brst
Original article
Discordance in early breast cancer for tumour grade, Estrogen Receptor, Progesteron Receptors and Human Epidermal Receptor-2 status between core needle biopsy and surgical excisional primary tumour Veronique Lorgis a, Marie Paule Algros c, Cristian Villanueva a, Loic Chaigneau a, Antoine Thierryvuillemin a, Thierry Nguyen a, Martin Demarchi a, Fernando Bazan a, Jean Loup Sautiere b, Yolande Maisonnette-Lescot b, Frederic Ringenbach c, Patrick Bontemps d, Xavier Pivot a, e, * a
University Hospital Jean Minjoz, Department of Medical Oncology, 25030 Besançon Cedex, France University Hospital Jean Minjoz, Department of Surgery, 25030 Besançon Cedex, France c University Hospital Jean Minjoz, Department of pathology, 25030 Besançon Cedex, France d University Hospital Jean Minjoz, Department of radiotherapy, 25030 Besançon Cedex, France e Institut National de la Santé et de la Recherche Médicale, Unit 645, 25000 Besançon, France b
a r t i c l e i n f o
a b s t r a c t
Article history: Received 17 May 2010 Received in revised form 20 November 2010 Accepted 23 December 2010
The aim of the present study was to compare the tumour grade, Estrogen Receptor (ER), Progesteron Receptor (PgR) and Human Epidermal Receptor-2 (HER-2) status in the core needle biopsy (CNB) with those observed in the subsequent excisional primary tumour (EPT). All patients diagnosed with an early breast cancer in our University Hospital Center between January 1, 2005 and December 31, 2006 were included but exclusion criteria of patients with large tumour requiring neoadjuvant chemotherapy and cases with more than one tumour (multicentricity/multifocality tumours). Histological tumour grade assessed according to Nottingham Grading System (SBRm), ER, Pgr and HER-2 tumoural status were assessed twice in CNB and in EPT. A total of 175 patients were assessed. The concordance between CNB and EPT for Grade, ER, PgR and HER2 status were 75.4% (p > 0.00001), 84% (p > 0.00002), 78.3% (p ¼ 0.002) and 98.3% (p ¼ 0.486) respectively. In conclusion CNB can be used with confidence for HER2 determination. For grade, PgR and ER due to substantial discordance results from CNB should be used with caution. Ó 2011 Elsevier Ltd. All rights reserved.
Keywords: Breast cancer Human epidermal receptor- 2 Estrogen receptor Progesteron receptor Tumoral prognostic and predictive factors
Introduction Prognostic and predictive factors such patient’s age, tumour size, axillary nodal involvement, histological tumour grade, Estrogen Receptor (ER), Progesteron Receptor (PgR) and Human Epidermal Receptor-2 (HER-2) tumoural status are critical in the decision making process for the determination of the need and the types of adjuvant treatments. It seems of interest to identify where those parameters would be accurately assessed. Taking into account that Core needle biopsy (CNB) has become a wellestablished diagnostic tool for both palpable and non-palpable
* Corresponding author. University Hospital Jean Minjoz, Department of Medical Oncology, 25030 Besançon Cedex, France. Tel.: þ33 3 8166 86 93; fax: þ33 3 8166 88 08. E-mail address: [email protected] (X. Pivot). 0960-9776/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved. doi:10.1016/j.breast.2010.12.007
breast cancers.1,2 An assessment on the CNB might provide an early determination of those prognostic and predictive factors allowing an early organisation of the subsequent adjuvant treatments. Nevertheless, a CNB may not accurately assess the histological tumour grade, ER, PgR and HER-2 tumoural status. Results from several studies have shown a wide variability in terms of concordance between CNB sample and excisional primary tumour (EPT) assessment.3e12 Concordances are ranged from 61% to 99% for ER, PgR and HER-2 status. Rare reports were focused on grade concordance despite its impact on the therapeutic decision.10,11,13 The aim of the present study was to compare the tumour grade, ER, PgR and HER-2 status in the CNB with those observed in the subsequent tumorectomy. The impact in terms of adjuvant therapy proposal was assessed prospectively during a multidisciplinary concertation meeting.
V. Lorgis et al. / The Breast 20 (2011) 284e287
Patients and methods Patients selection and methods All patients diagnosed with an early breast cancer in our university Hospital center between January 1, 2005 and December 31, 2006 were included. All patients with large tumour requiring neoadjuvant chemotherapy were excluded to avoid any changes on tumours characteristics due to treatment. All patients with multicentricity/multifocality tumours were excluded. The histological primary tumoral size, and axillary nodal involvement were assessed in the surgery samples. Histological tumour grade assessed according to Nottingham Grading System (SBRm), ER, Pgr and HER-2 tumoural status were assessed in CNB and in EPT. The fixation processing used formalin 4% and a superimposable method for both assessment in CNB and ETP. The major difference was the duration of fixation. From 12 to 24 h and 24 to 48 h for CNB and ETP specimens, respectively. ER and Pgr were determined by immuno histo chemistry (IHC) using Novocastra clone 6F11 antibody at dilution 1/20 and Dako clone PgR636 antibody at dilution 1/30 for ER and PgR, respectively. Those staining were assessed by Benchmarkt XT Ventana using i vieuwÔ DAB (Ventana). Results are expressed in terms of percent of stained tumoral cells with a cutoff for positivity higher than 10%. HER-2 assessment was scored from 0 to 3þ. HER-2 determination was done by IHC with Dako polyclonal C-erbB-2 oncoprotein antibody at dilution 1/1000 with a Benchmarkt XT Ventana using kit i vieuwÔ DAB (Ventana). In case of overexpression scored at 2þ, FISH (PathVysion; vysis) was performed to determine the amplification if the ratio of HER2 gene signal to chromosome 17 signal was >2. The grading, ER, PgR and HER2 status were performed by two pathologists and in case of disagreement the case were reassessed by discussion A multidisciplinary concertation meeting was organised to determine the adjuvant treatment based on the following parameters: patient’s age, histological tumoral size, axillary nodal involvement, histological tumour grade, ER, PgR and HER2 status. The determination of adjuvant treatment was done twice for each patient with histological grade, ER, PgR and HER2 status determined from CNB or from EPT. Those adjuvant treatment proposal were performed randomly and the origin of the determination was blinded. The multidisciplinary concertation meeting included 4 medical oncologists, two pathologists, one radiotherapist and two surgeons.
285
The main disease characteristics including tumour sizes, TNM, axillary nodal involvement, histological types were reported in Table 1. Moreover the histological tumour grade, ER, PR and HER2 status assessed in CNB and in EPT were described in Tables 1 and 2. It was notable that a higher proportion of tumours were diagnosed as grade III in EPT than in CNB (4% versus 20%, respectively; p < 0.0001). The large majority of difference was linked to mitoses assessment, they were scored three in 4 versus 28 cases in CNB and EPT, respectively. A concordance rate of 75.4% was observed for grade determination between CNB and EPT. Of interest among the 92 tumours treated by neoadjuvant chemotherapy 24 were grade III (26%). ER was scored positive in 159 in the CNB (90.9%) versus 139 in the EPT (79.4%) (p ¼ 0.002). There was concordance between ER assessment in 84% of cases with discrepancy in 20 tumours. In 16 cases the assessment in EPT was found ER negative whereas the evaluation in CNB was positive. For PgR in the CNB, 142 (81.1%) were scored positive compared with 106 (60.6%) in the EPT (p < 0.00001). The concordance rate for PgR was 78.3%. In all cases the assessment in EPT was found ER negative whereas the evaluation in CNB was positive but one. HER2 was overexpressed in 12 tumours (7%) according to the assessment in CNB. Of interest, among the 92 tumours treated by neoadjuvant chemotherapy, 21 were HER2 positive (22.8%). No significant discrepancy was observed (p > 0.05). Nevertheless 3 variations were observed: 2 tumours HER2 positive in CNB were found to be HER2 negative in EPT and 1 tumour HER2 negative in CNB switch to positivity in EPT. The concordance rate was 98.3%. A multidisciplinary concertation meeting based on CNB or EPT analysis resulted on a 16.5% divergence rate for adjuvant treatments. In the subset of patients without nodal involvement, the variation rates reached 32%. Interestingly, among the 28 discrepant cases for RE, patients were treated by hormonotherapy in 22 cases. Discussion CNB is widely accepted in routine assessment for the diagnosis of breast cancer. It is a reliable method for histological diagnosis and it provides enough material to allow determination for additional markers such ER, PgR and HER2 status. Those analyses are critical due to their implications in the guidance of clinical adjuvant proposal. However it may be a concern if assessment in CNB could be less reliable than in EPT due to smaller size, heterogeneous
Table 1 Patients & tumours characteristics.
Statistical plan A descriptive analysis of the population was performed. Comparisons between tumour grades, ER, Pgr and HER2 status assessed in CNB and in EPT were done using Chi2 test. Adjuvant decision stated during the multidisciplinary concertation meeting was compared using a Chi2 test considering the origin of the assessment. Results Ninety-two patients were excluded due to a neoadjuvant strategy, 31 patients because the core needle biopsy found only in situ carcinoma, 3 cases because the excisional primary tumours showed only in situ carcinoma, and 3 and 10 cases because the primary tumour or the core needle biopsy didn’t allow IHC due to sample size, respectively. A total of 175 patients were assessed. The patients and treatment characteristics were summarised in Table 1.
Patients & tumour characteristics N ¼ 175 Median age (range) Histological subtype Nodal involvement Tumour size
RE þ RE PgR þ PgR HER2 þ HER2 Grade I Grade II Grade III Unknown
61 years (31e91) Ductal carcinoma Lobular carcinoma þ T1 T2 T3
157 18 95 80 118 50 7
(90%) (10%) (54%) (42%) (67.4%) (28.6%) (4%)
Core needle biopsy
Excisional primary tumour
P
159 16 142 33 11 164 40 123 7 5
139 36 106 69 10 165 50 85 35 5
P ¼ 0.002 P > 0.00002 P ¼ 0.486 P > 0.00001
286
V. Lorgis et al. / The Breast 20 (2011) 284e287
Table 2 Concordance between Core needle biopsy (CNB) and Excisional Primary Tumour (EPT) for tumour grade, ER, PgR and HER2 status.
Table 3 Recommendation for assessment of ER, PgR, HER2, tumour grade. Core needle biopsy
EPT/CNB þ Total
12 4 16
þ 24 135 159
Total 36 139
þ Total
32 1 33
35 105 142
69 106
þ Total
163 1 164
2 9 11
165 10
ER
HER2
ER
PgR PgR
HER2 Grade (SBRm)
Grade (SBRm) I II III Total
40 0 0 40
10 85 28 123
0 0 7 7
50 85 35
tumour status. This present study is one of the larger published series assessing Grade, ER, PgR and HER2 status in CNB and in EPT in the same group of patients. A good concordance was found between CNB and EPT for ER status with a tendency of a higher ER positive determination in CNB.12 Similarly, a trend for upscoring in CNB compared with EPT has been commonly reported by previous studies. The trend for PgR to be distributed more heterogeneously within the tumour might explain the higher discrepancy observed for PgR between CNB and EPT in our study.14 Similarly, previous studies suggest that the concordance rate between CNB and EPT is higher for ER than for PgR. In this present study the only difference between the analysis of CNB and EPT was related to the duration of fixation with the formalin 4%. Is this variable duration induced this discrepancy? HER2 assessment concordance was reported to be high between core and surgical specimen. Nevertheless, the evaluation could be altered in case of crush or retraction artefacts. Taking into account this point, the American Society of Clinical Oncology pointed out that CNBs with edge or retraction artefact involving the entire core should not be used as sample to interpret HER2.15 The same recommendation might be extended to the assessment of all markers detected by IHC. Surprisingly, the rate of tumours which overexpressed HER2 appeared to be lower in the present study than previous report. In primary breast cancer the rate of HER2 positive tumour is dramatically inferior than the rate of 20% reported in metastatic setting. In the Franche Comte Region (France) an independent assessment of HER2 status in primary tumour established that 10.6% of cases present an overexpressed HER2 status. Discrepancy with the present study might be explained by the non-inclusion of patients treated by neoadjuvant chemotherapy where the tumour’s HER2 positivity incidence was 22.8%. The small number of HER2 positive cases in the studied cohort might be insufficient to allow judgement to be made of assessment on core biopsy Interestingly the underscore in terms of grade III identification in CNB versus EPT appeared to be significant. This could be explained by the smaller sample size analysed in CNB versus EPT. This result suggest that grade determination need to be performed in the EPT. This discrepancy would be of substantial importance since it would imply a major change in adjuvant treatments. Thus, the variabilities in term of adjuvant treatment proposal were 16.5% and reached 32% among the subset of patient without axillary nodal involvement. The impact of the grade, ER, PgR and HER2 status discordance need to be taken into account.
Excisional primary tumour
Yes Yes Excluding CNBs with edge or retraction artefact involving the entire core Yes Yes Taking into account an upscoring in 16% of cases for CNB versus EPT Yes Yes Taking into account an upscoring in 22% of cases for CNB versus EPT Yes Yes Diagnosis of grade III in CNB is valuable, in other cases a re-assessment on EPT was required
In conclusion, one needs to take into account those discrepancies and to establish recommendations aimed to increase the accuracy for the determination of those prognostic or predictive factors. One can state that HER2 status could be perform either on CNB or on EPT. The recommendation of the American Society of Clinical Oncology excluding CNBs with edge or retraction artefact involving the entire core should being the rule. For PgR and ER due to substantial discordance results from CNB should be used with caution. One can consider reasonable to recommend a systematic second assessment of ER, PgR status. Grade criteria might always been determined on the EPT but a grade III is identified on the CNB. Those recommendations are listed in Table 3. The interest of an early determination of those prognostics and predictive parameters on the CNB is altered by discrepancies. This point suggests caution in interpretation of those results to state for the need of adjuvant treatment. Conflict of interest Xavier Pivot perceived Honorarium from Roche SA, Glaxo SmithKline and Novartis. Cristian Vilanueva perceived honorarium from Amgen and Sanofi Aventis. Loic Chaigneau, and Thierry Nguyen perceived honorarium from Sanofi Aventis. There is however no conflict of interest in regard to the content of this contribution. References 1. Benson SR, Harrison NJ, Lengyel J, Deacon C, Isgar B. Combined image guidance excision of non-palpable breast lesions. Breast 2004;13:110e4. 2. Verkooijen HM, Peeters PH, Pijnappel RM, Koot VC, Schipper ME, Borel Rinkes IH. Diagnostic accuracy of needle-localized open breast biopsy for impalpable breast disease. Br J Surg 2000;87:344e7. 3. 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;184:322e4. 4. Sutela A, Vanninen R, Sudah M, Berg M, Kiviniemi V, Rummukainen J, et al. Surgical specimen can be replaced by core samples in assessment of ER, PR and HER-2 for invasive breast cancer. Acta Oncol 2008;47:38e46. 5. Taucher S, Rudas M, Mader RM, Gnant M, Dubsky P, Roka S, et al. Prognostic markers in breast cancer: the reliability of HER2/neu status in core needle biopsy of 325 patients with primary breast cancer. Wien Klin Wochenschr 2004;116:26e31. 6. Gotzinger P, Gebhard B, Gnant M, Rudas M, Reiner A, Jakesz R. [Value of punch biopsy in diagnosis of palpable breast tumors. A prospective analysis of 150 patients]. Chirurg 1998;69:1068e71. 7. Hodi Z, Chakrabarti J, Lee AH, Ronan JE, Elston CW, Cheung KL, et al. The reliability of assessment of oestrogen receptor expression on needle core biopsy specimens of invasive carcinomas of the breast. J Clin Pathol 2007;60:299e302. 8. Harris K, Morafa I, Thomas V, Mokbel K. Core biopsy is accurate in determining the hormone receptor status of early breast cancer. Am J Surg 2004;187:568. author reply 568. 9. Cavaliere A, Sidoni A, Scheibel M, Bellezza G, Brachelente G, Vitali R, et al. Biopathologic profile of breast cancer core biopsy: is it always a valid method? Cancer Lett 2005;218:117e21.
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