Synchronous Axillary Lymph Node Metastases Research Articles

Discordance of Biomarker Expression Profile between Primary Breast Cancer and Synchronous Axillary Lymph Node Metastasis in Preoperative Core Needle Biopsy

Background: Breast cancer (BC) is a heterogeneous disease made up of clones with different metastatic potential. Intratumoral heterogeneity may cause metastases to show divergent biomarker expression, potentially affecting chemotherapy response. Methods: We investigated the immunohistochemical (IHC) and FISH profile of estrogen receptors (ER), progesterone (PR) receptors, Ki67, and HER2 in a series of BC-matched primary tumors (PTs) and axillary lymph node (ALN) metastases in pre-operative core needle biopsies (CNBs). Phenotypical findings were correlated to morphological features and their clinical implications. Results: Divergent expression between PTs and ALNs was found in 10% of the tumors, often involving multiple biomarkers (12/31, 39%). Most (52%) displayed significant differences in ER and PR staining. HER2 divergences were observed in almost three-quarters of the cases (23/31, 74%), with five (16%) switching from negativity to overexpression/amplification in ALNs. Roughly 90% of disparities reflected significant morphological differences between PTs and ALN metastases. Less than half of the discrepancies (12/31, 39%) modified pre/post-operative treatment options. Conclusions: We observed relevant discrepancies in biomarker expression between PTs and metastatic ALNs in a noteworthy proportion (10%) of preoperative BC CNBs, which were often able to influence therapies. Hence, our data suggest routine preoperative assessment of biomarkers in both PTs and ALNs in cases showing significant morphological differences.

Clinical relevance of biomarker discordance between primary breast cancers and synchronous axillary lymph node metastases

Clinical decision-making for patients with breast cancer (BC) is still primarily based on biomarker characteristics of the primary tumor, together with the evaluation of synchronous axillary lymph node metastasis (LNM). In this study, we investigated the prevalence of discordance in the biomarkers and surrogate subtyping between the primary BC and the LNM, and whether subsequent changes would have altered clinical treatment recommendations. In this retrospective study, 94 patients treated for unifocal primary BC and synchronous LNM at Sahlgrenska UniversityHospital during 2018 were included. Estrogen (ER) and progesterone (PR) receptor, Ki67, and HER2 status were assessed in the primary tumor and LNM using immunohistochemistry. Discordances between the primary tumor and the LNM were analyzed for each individual biomarker and surrogate subtyping. The concordance between the primary tumor and the LNM for ER, PR, Ki67, and HER2 status was 98.9%, 89.4%, 72.3%, and 95.8%, respectively. Discordance in surrogate subtyping was found in 28.7% of the tumors and matched LNMs, the majority (81.5%) of which changed to a more favorable subtype in the LNM; most commonly from Luminal B to Luminal A (48.6%). No changes in surrogate subtyping were detected where ER or HER2 status changed from negativity in the BC to positivity in the LNM, thereby showing no additional value in performing immunohistochemistry on the LNM from a treatment decision-making perspective. However, large studies need to be performed that test both the primary BCs and synchronous LNMs for more accurate diagnostics.

In search for new targets: Differences of HER2 receptor expression between CNB and synchronous axillary lymph node metastases in 205 patients.

e12559 Background: Lately large clinical trials have provided new treatment options for patients with metastatic HER2-low breast cancer. Studies have shown that there may be change in the expression of HER2 during disease progression. Yet, it is rarely considered that there can be already differences between primary tumor and synchronous lymph node metastases (LMN) in the primary setting. The aim of the present study was to analyze different HER2 expression profiles between primary tumor and synchronous LNM. Methods: We included 205 patients with primary breast cancer and LNM who underwent oncologic surgery between 2008 and 2021. Formalin-fixed and paraffin-embedded (FFPE) material were routinely examined immunohistochemically according to the ASCO guidelines. Membranous HER2-staining was scored as follows: zero = 0, low = 1+, equivocal = 2+ and positive = 3+. Results: 205 patients were either HER2 low or HER2 zero in CNB. When comparing CNB and LNM 5 (2,4%) patients were HER2 zero in CNB and HER2 low in LNM. 161 (78.5%) patients were HER2 zero in both CNB and LNM. 21 (10.2%) patients had a shift from HER2 low to HER2 zero in LNM. 18 (8,8%) patients had a HER2 low expression in CNB and HER2 zero expression in LNM. Conclusions: There seems to be a high frequency of HER2 heterogeneity between primary tumor and LNM in the primary setting. Different HER2 expression profiles should be considered for an optimal and individual treatment.

Heterogeneity between Core Needle Biopsy and Synchronous Axillary Lymph Node Metastases in Early Breast Cancer Patients-A Comparison of HER2, Estrogen and Progesterone Receptor Expression Profiles during Primary Treatment Regime.

Simple SummaryAll initial therapeutic decisions in early breast cancer are commonly based on the intrinsic subtype consisting of estrogen (ER), progesterone (PR), the human epidermal growth factor 2 (HER2) receptors and the proliferation marker Ki67. However, breast cancer is a very heterogeneous disease, and receptor expression is reported to change during progression. Little is known about receptor changes at the primary site. In a German single center study, we retrospectively analyzed a mostly therapy naive cohort of 215 primary breast cancer patients with axillary synchronous lymph node metastases (LNM). We compared core needle biopsy tissue of the primary tumor (t-CNB) to axillary LNM and detected receptor discordance for all three receptors at the primary site.In breast cancer therapeutic decisions are based on the expression of estrogen (ER), progesterone (PR), the human epidermal growth factor 2 (HER2) receptors and the proliferation marker Ki67. However, only little is known concerning heterogeneity between the primary tumor and axillary lymph node metastases (LNM) in the primary site. We retrospectively analyzed receptor profiles of 215 early breast cancer patients with axillary synchronous LNM. Of our cohort, 69% were therapy naive and did not receive neoadjuvant treatment. Using immunohistochemistry, receptor status and Ki67 were compared between core needle biopsy of the tumor (t-CNB) and axillary LNM obtained during surgery. The discordance rates between t-CNB and axillary LNM were 12% for HER2, 6% for ER and 20% for PR. Receptor discordance appears to already occur at the primary site. Receptor losses might play a role concerning overtreatment concomitant with adverse drug effects, while receptor gains might be an option for additional targeted or endocrine therapy. Hence, not only receptor profiles of the tumor tissue but also of the synchronous axillary LNM should be considered in the choice of treatment.

Intertumoral Heterogeneity of Primary Breast Tumors and Synchronous Axillary Lymph Node Metastases Reflected in IHC-Assessed Expression of Routine and Nonstandard Biomarkers

Breast cancer (BC) remains a significant healthcare challenge. Routinely, the treatment strategy is determined by immunohistochemistry (IHC)-based assessment of the key proteins such as estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2), and Ki-67. However, it is estimated that over 75% of deaths result from metastatic tumors, indicating a need to develop more accurate protocols for intertumoral heterogeneity assessment and their consequences on prognosis. Therefore, the aim of this preliminary study was the identification of the expression profiles of routinely used biomarkers (ER, PR, HER2, Ki-67) and additional relevant proteins [Bcl-2, cyclin D1, E-cadherin, Snail+Slug, gross cystic disease fluid protein 15 (GCDFP-15), programmed death receptor 1 (PD-L1), and phosphatase of regenerating liver 3 (PRL-3)] in breast primary tumors (PTs) and paired synchronous axillary lymph node (ALN) metastases. A total of 67 tissue samples met the inclusion criteria for the study. The expression status of biomarkers was assessed in PTs and ALN metastases using tissue microarrays followed by IHC. In 11 cases, the shift of intrinsic molecular BC subtype was noticed between PTs and paired ALN metastases. Moreover, a significant disproportion in E-cadherin presence (p = 0.0002) was noted in both foci, and the expression status of all proteins except for HER2 demonstrated considerable variance (k = 1, p < 0.0001). Importantly, in around 30% of cases, the ALN metastases demonstrated discordance, i.e., loss/gain of expression, compared to the PTs. Intertumoral synchronous heterogeneity in both foci (primary tumor and node metastasis) is an essential phenomenon affecting the clinical subtype and characteristics of BC. Furthermore, a greater understanding of this event could potentially improve therapeutic efficacy.

Heterogeneity between core needle biopsy and synchronous axillary lymph node metastases in early breast cancer patients: Comparison of HER2, estrogen and progesterone receptor expression profiles during primary treatment regime.

e12565 Background: Therapeutic decisions for the primary treatment of breast cancer is commonly based on the expression profiles of estrogen (ER), progesterone (PR) and the human epidermal growth factor 2 (HER2) receptors. However, breast cancer is a very heterogeneous disease, and receptor changes were manifold reported during progression. Little is known about receptor discordance in the primary setting. Here, we compared receptor expression profiles between core needle biopsy (CNB) of the breast tumor tissue and synchronous axillary lymph node metastases (LNM) not at recurrence, but at the primary treatment. Methods: In a German single center study, we retrospectively analyzed 175 breast cancer patients with axillary synchronous LNM. 69,7% of our patients were without any upfront therapy. Profiles of ER, PR and HER2 were immunohistochemically analyzed using the common cut-off at 10% positive tumor cells vs. the controversially discussed low-positive cut-off at 1%. Receptor status was compared between CNB specimens of the primary tumor tissue and axillary LNM. Further, clinicopathological characteristics were correlated to receptor changes. Results: The discordance rates between CNB and axillary LNM were 12.7% for HER2, 6.9% for ER and 22.6% for PR using the ≥1% cut-off, respective 7.5% for ER and 25.6% for PR when using the ≥10% cut-off-level. The most frequently occurring change was a PR loss. Analysis of clinical parameters revealed a significant association of ER change between CNB and LNM in younger patients (p &lt; 0.01) with increased proliferation marker Ki-67 (p = 0.04). Conclusions: Receptor discordance between CNB and synchronous axillary LNM appears to exist at the primary setting already. Hence, receptor profiles of the tumor tissue and the synchronous axillary LNM should be considered for treatment decision.

Clinical impact of the biology of synchronous axillary lymph node metastases in primary breast cancer on preoperative treatment strategy.

The purpose of this study was to assess the utility of determining the biological features of synchronous axillary lymph node (syLN) metastasis of breast cancer in evaluating the efficacy of preoperative systemic chemotherapy (PST). The retrospective subjects initially comprised 59 patients (T1c-4 N1-3 M0) diagnosed with syLN metastasis via core needle biopsy who received PST. The hormone receptor (HR) and human epidermal growth factor receptor 2 (HER2) status in each patient was assessed in primary breast tumor (pBT) and syLNs using immunohistochemistry, and the patients were classified into HR(+), HER2(+), and triple negative breast cancer (TN) subtypes. Subtype shift (SS) of pBT in syLNs was observed in 28% cases for HR(+), in 6% cases for the HER2(+), and in 16% cases for the TN. The pCR rate of the pBT and syLNs types were 45% and 36% in the HR(+), 45% and 39% in the TN, and 94% and 100% in the HER2(+), respectively. In SS cases, the pCR rate was significantly higher in 75% cases compared with 33% of the no-SS cases. A SS in syLNs was more frequent in HR(+) than in other types.

Biomarker heterogeneity between primary breast cancer and synchronous axillary lymph node metastases.

Whether the expression status of estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER-2) receptor and Ki-67 show concordance between the primary tumors and the synchronous axillary lymph node (ALN) metastases has been discussed in numerous studies. However, to date, the results of these studies remain controversial. Therefore, the present study aimed to investigate whether the expression of ER, PR, HER-2 and Ki-67 was in concordance between the primary tumors and synchronous ALN metastases in patients with operable breast cancer (BC). A total of 60 tissue samples were collected from patients with primary operable BC diagnosed with primary tumors and synchronous ALN metastases. The expression levels of the four biomarkers, ER, PR, HER-2 and Ki-67, were assessed in primary lesions and synchronous ALN metastases samples using immunohistochemistry. The cut-off values were set to 10% for ER and PR, while the labeling index of Ki-67 was set to 14%. The immunostaining intensity of ER and PR was scored as negative (−), 1+, 2+ and 3+. The criteria for HER-2 testing in BC were implemented according to the American Society of Clinical Oncology (ASCO) and the College of American Pathologists (CAP) guidelines. The concordance rates for ER, PR and HER-2 were 96.7 (58/60), 96.7 (58/60) and 90% (54/60), respectively. In addition, the kappa values of consistency in the primary lesions and the synchronous ALN metastases were 0.773 for ER, 0.654 for PR and 0.785 for HER-2. Furthermore, the P-values of ER, PR and Ki-67 numerical variables between the two groups were 0.393, 0.400 and 0.331, respectively, as demonstrated using a non-parametric Wilcoxon signed rank test. The findings of the present study demonstrated a high degree of concordance between the expression of ER, PR, HER-2 and Ki-67 in the primary tumors and that in the synchronous ALN metastases, suggesting that the BC primary tumor biomarkers may be used for the prognosis of synchronous ALN metastases in patients with operable BC.

Abstract P4-06-06: Comparison of HER2, estrogen and progesterone receptor expression profiles of primary tumor and synchronous axillary lymph node metastases in 149 breast cancer patients - indicating tumoral heterogeneity

Abstract Background: Tumor heterogeneity in terms of comparison between receptor expression profiles (ER, PR and HER2) of primary core needle biopsies (CNB) and definitive lymph node histo-pathologic examination is an evolving research field with unknown potential in terms of individual oncological treatment. Yet, heterogeneity is merely common as a different receptor expression between primary tumor versus metastatic disease. Thus, data on primary receptor heterogeneity between primary tumor and synchronous lymph node metastasis is rare. Primary aim of this trial is to present data on the epidemiologic aspect of tumor heterogeneity with synchronous lymph node metastases (LNM) in breast cancer patients. Methods: We retrospectively analyzed 149 consecutive patients with breast cancer and synchronous LNM who undergone oncologic surgery (sentinel lymph-node biopsy: 66,4%, axillary lymph-node dissection: 33,6%) between 2008 and 2018 at the university hospital Leipzig, Germany. Patients underwent operation without any preoperative therapy, with neoadjuvant chemotherapy or with neoadjuvant hormone therapy in 109 (73,2%), 30 (20,1%) and 10 (6,7%) cases, respectively. Formalin-fixed and paraffin-embedded (FFPE-material) were routinely examined immunohistochemically according to the ASCO/CAP guidelines using Ventana-platform. The results for ER, PR and HER2 were analyzed case-by-case comparing results from the CNB of the primary tumor within the breast and axillary LNM. Proliferative activity was determined by MIB-1 immunohistochemistry and according to well established guidelines, the tumors were grouped into the different intrinsic subtypes as luminal A and B, HER2-enriched and triple-negative by the different immunohistochemical staining results. Results: Median patient age was 61 years with most frequent tumor entity (75,8%) being an invasive-ductal adeno carcinoma. 115 (77,2%) patients had either a T1 or T2 stadium. Overall there were 61 (40,1%) patients who had at least one receptor change, with 16 patients with two receptor changes. The discordance rates between primary tumors and axillary LNM were 13,4% for HER2, 10,1% for ER and 28,2% for PR. Totally in 69 receptor changes the receptor was initially positive and changed to negative (receptor-loss), whilst in 8 cases a receptor was positive that was initially negative (receptor-gain). Out of 77 receptor changes, 18 were after neoadjuvant chemotherapy, 5 after neoadjuvant endocrine therapy and 54 changes were without any neoadjuvant treatment. Influencing factor in estrogen receptor changes in the competitive analysis was a younger age (p-value 0.01, medium age 51.27 years; PR receptor change, medium age: 60,88 years; HER2 receptor change: medium age: 61,65 years). Conclusions: Our results imply the high frequency of subtype differences between primary tumor and LNM. This could be explained by intra-tumor heterogeneity. Subtype changes should be taken into account for an optimal and individual treatment. Larger studies are necessary to validate these data and gain further information. Citation Format: Laura Weydandt, Anne Kreklau, Florian Oehme, Lars Christian Horn, Bahriye Aktas. Comparison of HER2, estrogen and progesterone receptor expression profiles of primary tumor and synchronous axillary lymph node metastases in 149 breast cancer patients - indicating tumoral heterogeneity [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P4-06-06.

Hormone receptor, human epidermal growth factor receptor-2, and Ki-67 status in primary breast cancer and corresponding recurrences or synchronous axillary lymph node metastases.

The therapeutic strategy for breast cancer is determined by the surrogate subtype, which is defined by biomarkers, such as estrogen receptor (ER), progesterone receptor (PgR), human epidermal growth factor receptor-2 (HER2), and Ki-67. In previous reports, the rate of discordance in ER, PgR, and HER2 between primary breast cancer and recurrent lesions or synchronous axillary lymph node metastasis was 15-25, 25-40, and 5-25 or 7-50, 10-50, and 3-30%, respectively. Overall, hormone receptors tended to weaken during the metastatic process, while patterns of HER2 were not uniform. Regarding the Ki-67 labeling index, an increase in metastatic lesions compared with primary lesions was the dominant pattern, suggesting that aggressive subclones with high proliferative potential form metastases. The loss of expression of hormone receptor or an increase in the Ki-67 labeling index in metastasis seemed to be associated with a poor prognosis. However, most previous studies did not report the background characteristics of patients, or they included subjects with varied characteristics, including those on systemic therapy, and were based on relatively small populations; therefore, definitive conclusions could not be drawn. Future studies should explore how to select therapies according to the biomarkers in primary breast cancer and/or its metastasis.

34P - Comparison of HER2, estrogen and progesterone receptor expression profiles of primary tumor and synchronous axillary lymph node metastases in 159 breast cancer patients - indicating tumoral heterogeneity

34P - Comparison of HER2, estrogen and progesterone receptor expression profiles of primary tumor and synchronous axillary lymph node metastases in 159 breast cancer patients - indicating tumoral heterogeneity

Abstract PD3-02: Comparison of HER2, estrogen and progesterone receptor expression profiles of primary tumor, synchronous axillary lymph node metastases and circulating tumor cells in early breast cancer patients

Abstract Background:Targeted systemic therapy in early breast cancer with synchronous lymph node metastasis is currently based on the expression of the hormone receptors (ER/PR ≥1%) and overexpression of HER2 in the primary tumor. However, the expression of these predictive markers on lymph node metastases as well as on circulating tumor cells (CTCs), the precursors of metastatic disease, has not yet been taken into account. The aim of the present study was to compare the HER2/ER/PR expression profiles of primary tumors, synchronous lymph node metastases and circulating tumor cells in early breast cancer patients and relate the results to 5-year overall (OS) and disease-free survival (DFS). Patients and Methods:76 patients with early breast cancer diagnosed between 2006 and 2010 were enrolled in this study. Blood was obtained at the time of first diagnosis of disease and analyzed for CTCs using the AdnaTest BreastCancer (Qiagen Hannover GmbH) for the expression of EpCAM, MUC-1, HER2, ER and PR respectively. Formalin-fixed and paraffin-embedded archival tissues of the primary tumors and the lymph node metastases were analyzed by two pathologists. ER, PR and HER2 expression was assessed by fully-automated immunohistochemistry (Ventana medical Systems, USA) and HER2/CEN17 dual chromogenic in situ hybridization (Zytomed Systems, Germany) according to modified ASCO/CAP guidelines (2010 and 2013). The patients' cohort has been extended for the time period of 2010-2012. Results: 2006-2010 the detection rate for CTCs was 22% (17/76 patients). In the primary tumors, the expression rate of HER2 was 16% (13/76 patients), 78% for ER (61/76 patients) and 75% for PR (57/76 patients) respectively. Changes in biomarker profiles between primary tumors, metastases and CTCs, as a whole, were observed in 89% of the cases (68/76). The discordance rates between primary tumors and lymph node metastases were 10% for HER2 (p&amp;lt;0.001), 5% for ER (p=p&amp;lt;0.001) and 11% for PR (p&amp;lt;0.001). The intrinsic subtypes between primary tumors and lymph node metastases changed in 16% of all cases (12/76 patients; gain of HER2 in four, activation of HRs in three cases, loss of HER2 in three and loss of HRs in one case becoming triple negative). Of note, both OS and DFS of patients with subtype discordance were reduced to a median of 41 months (mean:39) vs 56 months (mean:51). CTCs were either triple negative or HER2 positive. Discordance rates for HER2, ER and PR status compared to the primary tumors were 16% (12/76 patients), 83% (63/76 patients)and 72% (55/76 patients), respectively. Discordant rates between lymph node metastases and CTCs were 25% for HER2 (19/76 patients), 82% for ER (62/76 patients) and 72% for PR (55/76 patients). Enlarged results including the cohort 2010-2012 will be available for SABCS 2017. Conclusion: Our preliminarily results demonstrate, that changes in molecular profiles are the rule rather than the exception throughout tumor progression in breast cancer. In cases with discordant biomarker profiles, prognosis seems to follow the subtype of lymph node metastasis. Biomarker or subtype shift may be of essential therapeutic significance for individual patients. Citation Format: Aktas B, Weydandt L, Westerwick D, Mairinger F, Kasimir-Bauer S, Kimmig R, Schmid K, Bankfalvi A. Comparison of HER2, estrogen and progesterone receptor expression profiles of primary tumor, synchronous axillary lymph node metastases and circulating tumor cells in early breast cancer patients [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr PD3-02.

Heterogeneity of PD-L1 expression in primary tumors and paired lymph node metastases of triple negative breast cancer

BackgroundProgrammed cell death ligand 1 (PD-L1) is a potential predictive biomarker of the response to anti-PD-L1/anti- programmed cell death 1 (PD-1) therapy in multiple cancers, including triple negative breast cancer(TNBC). The purpose of this study was to investigate whether PD-L1 expression is homogenous in primary tumors(PTs) and synchronous axillary lymph node metastases(LNMs) of TNBC.MethodsPD-L1 expression was immunohistochemically evaluated in 101 TNBC patients’ PTs and paired LNMs. PD-L1 expression in tumor cells and infiltrating immune cells or node lymphocytes in the PTs and associated LNMs was scored separately and was correlated with patients’ clinical parameters and prognoses.ResultsPD-L1 expression exhibited spatial heterogeneity in both the tumor cells and the infiltrating immune cells or node lymphocytes of PTs and LNMs. The PD-L1 expression levels were significantly higher in the lymphocytes and tumor cells of the LNMs than in the PTs. PD-L1 expression was also more frequent among the LNMs. PD-L1 expression was associated with high grade and more stromal tumor-infiltrating lymphocytes(TILs). Furthermore, the disease-free survival and overall survival were similar between the PT- negative/LNM- positive and PT- positive/LNM- positive patients, both of which exhibited worse disease-free survival(DFS) thanPT -negative/LNM -negative patients.ConclusionsThe differential expression of PD-L1 between the PTs and LNMs suggests that LNMs PD-L1 status may be used to indicate whether PD-1/PD-L1-targeted therapy would be suitable for a node-positive TNBC patient in the future.

Abstract P1-01-09: Comparison of HER2, estrogen and progesterone receptor expression profiles of primary tumor, synchronous axillary lymph node metastases and circulating tumor cells in early breast cancer patients

Abstract Background:Targeted systemic therapy in early breast cancer with synchronous lymph node metastasis is currently based on the expression of the hormone receptors (ER/PR ≥1%) and overexpression of HER2 in the primary tumor. However, the expression of these predictive markers on lymph node metastases as well as on circulating tumor cells (CTCs), the precursors of metastatic disease, has not yet been taken into account. The aim of the present study was to compare the HER2/ER/PR expression profiles of primary tumors, synchronous lymph node metastases and circulating tumor cells in early breast cancer patients and relate the results to 5-year overall (OS) and disease-free survival (DFS). Patients and Methods:76 patients with early breast cancer diagnosed between 2006 and 2010 were enrolled in this study. Blood was obtained at the time of first diagnosis of disease and analyzed for CTCs using the AdnaTest BreastCancer (Qiagen Hannover GmbH) for the expression of EpCAM, MUC-1, HER2, ER and PR respectively. Formalin-fixed and paraffin-embedded archival tissues of the primary tumors and the lymph node metastases were analyzed by two pathologists. ER, PR and HER2 expression was assessed by fully-automated immunohistochemistry (Ventana medical Systems, Tucson, AZ, USA) and HER2/CEN17 dual chromogenic in situ hybridization (Zytomed Systems, Berlin, Germany) according to modified ASCO/CAP guidelines (2010 and 2013, respectively). Results: The detection rate for CTCs was 22% (17/76 patients). In the primary tumors, the expression rate of HER2 was 16% (13/76 patients), 78% for ER (61/76 patients) and 75% for PR (57/76 patients) respectively. Changes in biomarker profiles between primary tumors, metastases and CTCs, as a whole, were observed in 89% of the cases (68/76). The discordance rates between primary tumors and lymph node metastases were 10% for HER2 (p&amp;lt;0.001), 5% for ER (p= p&amp;lt;0.001) and 11% for PR (p&amp;lt;0.001). The intrinsic subtypes between primary tumors and lymph node metastases changed in 16% of all cases (12/76 patients; gain of HER2 in four, activation of HRs in three cases, loss of HER2 in three and loss of HRs in one case becoming triple negative). Of note, both OS and DFS of patients with subtype discordance were reduced to a median of 41 months (mean: 39) vs 56 months (mean: 51). CTCs were either triple negative or HER2 positive. Discordance rates for HER2, ER and PR status compared to the primary tumors were 16% (12/76 patients), 83% (63/76 patients)and 72% (55/76 patients), respectively. Discordant rates between lymph node metastases and CTCs were 25% for HER2 (19/76 patients), 82% for ER (62/76 patients) and 72% for PR (55/76 patients). Conclusion: Our preliminarily results demonstrate, that changes in molecular profiles are the rule rather than the exception throughout tumour progression in breast cancer. In cases with discordant biomarker profiles, prognosis seems to follow the subtype of lymph node metastasis. Biomarker or subtype shift may be of essential therapeutic significance for individual patients. Citation Format: Aktas B, Westerwick D, Mairinger F, Kasimir-Bauer S, Kimmig R, Schmid K, Bankfalvi A. Comparison of HER2, estrogen and progesterone receptor expression profiles of primary tumor, synchronous axillary lymph node metastases and circulating tumor cells in early breast cancer patients [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P1-01-09.

Discordance Rate in Estrogen Receptor, Progesterone Receptor, HER2 Status, and Ki67 Index Between Primary Unifocal and Multiple Homogenous Breast Carcinomas and Synchronous Axillary Lymph Node Metastases Have an Impact on Therapeutic Decision.

Background:We aimed to demonstrate that in breast carcinomas the tumor profile is not stable during the metastatic process, with impact on therapeutic decisions.Materials and Methods:We analyzed the estrogen receptor (ER), progesterone receptor (PR), and HER2 status and Ki67 index in 41 primary unifocal (PU) and 37 primary multiple (PM) breast carcinomas with identical immunohistochemical profiles among multiple tumor foci and the matched axillary lymph node metastases. We defined as concordant cases in which the primary tumor (PU or PM) and lymph node metastases displayed identical positivity or negativity for ER, PR, HER2, Ki67 and as discordant cases in which there was a mismatch in at least 1 biological parameter among PU and PM tumor and lymph node metastases. Moreover, we defined as concordant cases in which the molecular profile (based on the immunohistochemical evaluation of ER, PR, HER2, and Ki67) was concordant among PU and PM tumors and lymph node metastases and mismatch cases as those in which the molecular profile of the primary tumor differs from one of the lymph node metastases in at least 1 lymph node.Results:The positivity for the biological markers is not stable during the metastatic process. In this study the total rate of discordant cases was 92.7% in PU tumors and 75.7% in PM homogenous tumors (P=0.058, odds ratio=0.245, 95% confidence interval, 0.06-0.991). The total rate of shifted cases was 64.9% in PM tumors and 82.9% in PU tumors. The highest rate of shifting was encountered from Luminal B-like to Luminal A-like. In 11 out of 37 (29.7%) PM and in 17 out of 41 (41.5%) PU cases the subtype shifted to a poorer one with respect to prognosis.Conclusions:The patients in whom the primary tumor is hormone receptor and/or HER2 negative but is positive for these markers in the axillary lymph nodes could become eligible for hormonal treatment and/or trastuzumab treatment, which may significantly improve the patient’s outcome.

Discordance of HER2 status between primary inflammatory breast cancer and synchronous axillary lymph node metastases

Discordance of HER2 status between primary inflammatory breast cancer and synchronous axillary lymph node metastases

Hormone receptors and HER2 expression in primary tumor and synchronous axillary lymph node metastasis in estrogen receptor positive breast cancer.

e11580 Background: The receptor status, Estrogen Receptor (ER), Progesterone Receptor (PR) and HER-2 can change between the primary (P) and the synchronous axillary lymph node (ALN) metastases. The...

Changes in glycoprotein expression between primary breast tumour and synchronous lymph node metastases or asynchronous distant metastases.

BackgroundBreast cancer is a very heterogeneous disease and some patients are cured by the surgical removal of the primary tumour whilst other patients suffer from metastasis and spreading of the disease, despite adjuvant therapy. A number of prognostic and treatment predictive factors have been identified such as tumour size, oestrogen (ER) and progesterone (PgR) receptor status, human epidermal growth factor receptor type 2 (HER2) status, histological grade, Ki67 and age. Lymph node involvement is also assessed during surgery to determine if the tumour has spread which requires dissection of the axilla and adjuvant treatment. The prognostic and treatment predictive factors assessing the nature of the tumour are all routinely based on the status of the primary tumour.ResultsWe have analysed a unique tumour set of fourteen primary breast cancer tumours with matched synchronous axillary lymph node metastases and a set of nine primary tumours with, later developed, matched distant metastases from different sites in the body. We used a pairwise tumour analysis (from the same individual) since the difference between the same tumour-type in different patients was greater. Glycopeptide capture was used in this study to selectively isolate and quantify N-linked glycopeptides from tumours mixtures and the captured glycopeptides were subjected to label-free quantitative tandem mass spectrometry analysis. Differentially expressed proteins between primary tumours and matched lymph node metastasis and distant metastasis were identified. Two of the top hits, ATPIF1 and tubulin β-chain were validated by immunohistochemistry to be differentially regulated.ConclusionsWe show that the expression of a large number of glycosylated proteins change between primary tumours and matched lymph node metastases and distant metastases, confirming that cancer cells undergo a molecular transformation during the spread to a secondary site. The proteins are part of important pathways such as cell adhesion, migration pathways and immune response giving insight into molecular changes needed for the tumour to spread. The large difference between primary tumours and lymph node and distant metastases also suggest that treatment should be based on the phenotype of the lymph node and distant metastases.Electronic supplementary materialThe online version of this article (doi:10.1186/s12014-015-9084-7) contains supplementary material, which is available to authorized users.

Discordance rate of HER2 status in primary breast carcinomas versus synchronous axillary lymph node metastases: a multicenter retrospective investigation

BackgroundHuman epidermal growth factor receptor 2 (HER2) is considered to be a therapeutic and prognostic marker in the management of breast carcinoma (BC), although discordance rates between primary and metastatic or locally recurrent lesions have been reported.MethodsOne hundred and forty-eight paraffin-embedded BC tissues from patients of mean age 59.27 (33–96) years and corresponding synchronous lymph node metastases were collected and retrospectively studied using immunohistochemistry and fluorescence in situ hybridization to evaluate HER2 status. Fleiss-Cohen weighted k statistics were used to assess the concordance rate between HER2 status of the primary BC and the synchronous metastatic lesions.ResultsThe overall concordance rate for HER2 was 95.28%. Eighty-nine cases were concordantly HER2-negative in primary BC and nodal metastases, and 52 cases were HER2-positive in both primary and metastatic tumors. Changes in HER2 status between primary BC and corresponding synchronous metastases were observed in seven (4.72%) cases. Three of the discordant cases were HER2-negative in the primary tumor and HER2-positive in the metastases, while four cases were HER2-positive in the primary BC and HER2-negative in the metastases. No significant correlations were identified between HER2 status and expression of hormone receptors, growth fraction (Ki-67), or other histopathological parameters (pT, pN, grade).ConclusionSimultaneous determination of HER2 in BC and corresponding metastatic lymph nodes is not mandatory, but may strongly influence the therapeutic management. It was demonstrated that loss of HER2 amplification results in worse post-relapse survival and overall survival in BC patients and, on the other hand, a gain in HER2 expression in metastatic lymph nodes of BC may allow the possibility of a targeted treatment. Thus, our opinion is that significant prognostic information may be obtained by simultaneous assessment of HER2 status in both primary and synchronous metastatic BC.

Discordance and clinical significance of ER, PR, and HER2 status between primary breast cancer and synchronous axillary lymph node metastasis

Discordance of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) status between primary breast cancer, metastatic lesion and synchronous axillary lymph node metastasis has been reported in the series studies. Systemic treatment of primary invasive breast cancer patients with synchronous axillary metastasis is currently based on the biomarker characteristics of the primary tumor; however, hormone receptors and HER2 status may change throughout tumor progression from the primary tumor to the synchronous axillary metastasis. As local metastasis, the synchronous axillary lymph node metastasis may represent the potentially metastatic breast cancer cells much better than the primary tumor. Hence, the determination of hormone receptors and HER2 status should be routinely performed in synchronous axillary nodal metastasis, together with primary tumor, to guide therapy management and evaluate the recurrent risk of primary invasive breast cancer patients with synchronous axillary nodal metastasis, which may even change the postoperative risk categories (St. Gallen consensus) of breast cancer in these patients. This article will review the studies on the discordance and clinical significance of ER, PR, and HER2 receptor status between primary breast cancer and synchronous axillary lymph node metastasis.