Receptor Discordance Research Articles

Clinical, pathological and gene expression profiling of estrogen receptor discordance in breast cancer.

Breast cancer (BC) is the world's largest tumor species in which hormone receptor-positive patients have relatively good prognosis. However, majority of patients will develop late resistance, one of the important factors is due to the loss of the original estrogen receptor (ER) expression. We conducted this study in 115 patients with BC who experienced second biopsy at Jiangsu Province Hospital (JSPH) and divided patients into two subgroups ER + to - and ER + to + . First, clinicopathological characteristics between two groups were evaluated. Second, we explored candidate genes related to BC ER intratumor heterogeneity by applying next-generation sequencing (NGS) in 42 patients. Multi-omics integrative analysis of tumor transcriptomic, cancer-related pathway, diagnostic and prognostic value and immune profile were conducted. Besides, preliminary assay were also used to evaluate the correlation between KMT2C and ERα (ESR1) expression. The CCK-8, 5-Ethynyl-2'-deoxyuridine (EdU) assays, Transwell assays and the wound scratch tests were applied to explore the cellular interactions between KMT2C and BC. We find the histological type (p = 0.008) and disease-free survival (DFS) (p = 0.004) were significantly different in two subgroups. In Cox survival analysis, metastasis (Hazard ratio (HR) > 1, p = 0.007) and neo-adjuvant (HR < 1, p < 0.001) are independent prognostic factors of DFS. Besides, by analyzing NGS results, we found four genes KMT2C, FGFR19, FGF1 and FGF4 were highly mutated genes in ER + to - subgroup. Furthermore, the gene KMT2C displayed significant diagnostic value and prognostic value in BC and pan-cancer. In addition, a positive correlation between KMT2C expression and immune infiltrating levels of T cell CD4 + , macrophage and neutrophil was found. In the end, Western blot and RT-qPCR assay were used and found KMT2C and ERα (ESR1) expressions are strongly positive correlated in mRNA and protein level. Inhibition of KMT2C significantly reduced proliferation, invasion, and migration of MCF7 cells. People in two cohorts from JSPH presented different clinical characteristics and prognosis. The gene KMT2C may affect the progression of BC by regulating the molecular, epigenetic activity and immune infiltration. It may also serve as a novel prognostic biomarker for BC patients who underwent ER status converted from positive to negative.

Does immunohistochemical marker conversion affect the prognosis in breast cancer patients receiving neoadjuvant chemotherapy?

Biomarkers such as hormone receptors (HR) and human epidermal growth factor receptor2 (HER2) may change after neoadjuvant chemotherapy (NAC) in breast cancer patients. The aim of this study was to investigate the rates of receptor change after NAC and to evaluate the prognostic impact of change. Patients with breast cancer who received NAC were included in the study. Changes in pathological findings (ER, PR, HER-2, Ki-67, grade) before and after NAC were examined. In addition, the effect of receptor exchange on prognosis was evaluated. Kaplan Meier analysis was used for survival analyses. Study was approved by Ethics Board of Tepecik Training and Research Hospital (Decision number 2021/10-02). We confirm that all methods were performed in accordance with relevant named guidelines and regulations. The study included 203 female patients. When pathological findings before and after NAC were compared, significant regression was found in grade and Ki-67 values (p = 0.003, p < 0.001). ER change rate was 11.8%, PR change rate was 24.6% and HER-2 change rate was 12.5%. No significant correlation was found between ER, PR and HER-2 changes and prognosis. The pathological T stage after NAC being 1 or 2, no lymph nodes detected, and the tumor grade being 1 or 2 were independent variables related to survival (p: 0.002, p: 0.014, p < 0.001). In patients with breast cancer, it would be appropriate to re-evaluate the HER-2 and HR status of the surgical specimen following NAC, especially in initially negative patients. The correlation of receptor discordance with prognosis is not clear and more extensive studies are needed.

Abstract PO3-03-11: Receptor discordance after neoadjuvant chemotherapy with pembrolizumab in early-stage triple-negative breast cancer

Abstract Background: Discordance in hormone receptor (HR) and/or HER2 status between matched primary tumors and residual specimens following neoadjuvant therapy is a known phenomenon. In the neoadjuvant setting, systemic treatment is primarily informed by the HR and HER2 status from the diagnostic biopsy. Current guidelines recommend additional adjuvant capecitabine and/or pembrolizumab and/or olaparib for patients with triple-negative breast cancer (TNBC) after neoadjuvant systemic therapy if residual disease is present at the time of surgery. Discordance in biomarker status between the initial diagnosis and residual cancer may impact postoperative systemic therapy recommendations. This study aims to investigate the discordance rate in HR and HER2 status after neoadjuvant chemotherapy (NAC) plus pembrolizumab in early-stage TNBC. Furthermore, given the emerging data in support of novel antibody-drug conjugates (ADCs) for HER2-low breast cancer, the prevalence of HER2-low disease following standard-of-care neoadjuvant therapy may have critical clinical importance. Methods: We performed a single-institution, retrospective study of early-stage TNBC patients diagnosed between February 1st, 2020 and December 1st, 2022 who were treated with neoadjuvant chemotherapy and pembrolizumab. Patients who had not undergone definitive surgery were excluded. Demographic information, clinical and pathologic characteristics, and treatment data were collected from an institutional database. Pathologic complete response (pCR) was defined as ypT0/Tis and ypN0. HR and HER2 status before and after neoadjuvant therapy were collected. This study was approved by an Institutional Review Board. Results: Among the 94 patients included the median age was 55 years (IQR 47.0-61.8). The majority of patients had invasive ductal carcinomas (90.4%), were clinical T2 stage (68.1%), and node negative (55.3%). On the core tumor biopsy, estrogen receptor (ER) was &amp;lt; 1% in 90 (95.7%) patients and 1-10% in 4 (4.3%) of patients. Progesterone receptor (PR) was &amp;lt; 1% in 91 (96.8%) of patients and 1-10% in 3 (3.2%) of patients. HER2 was 0 by IHC in 49 (52.1%) patients, 1+ in 30 (31.9%) patients, 2+ in 11 (11.7%) patients, and not performed in 4 (4.3%) patients. A pCR (ypT0/Tis ypN0) was achieved in 60 (63.8%) of the 94 patients. In the 34 patients with residual disease, 29 patients had ER status evaluated at the time of surgery. Of these patients, 4 had tumors with ER &amp;lt; 1% at baseline but &amp;gt;5% at surgery. 28 patients with residual disease had PR evaluated at the time of surgery. Of these patients, all had tumors with PR &amp;lt; 1% at the time of surgery. 28 patients had residual tumors with HER2 status evaluated at the time of surgery (table). Of these patients, 18 (64.3%) tumor specimens were HER2-ultra-low, 9 (32.1%) were HER2-low-positive, and 1 (3.6%) was HER2-positive. Conclusion: Receptor discordance from the time of initial biopsy to residual disease can occur in patients with early-stage TNBC treated with NAC with pembro. As additional systemic therapy is indicated in patients who do not achieve pCR, accurate tumor marker status is critical. This study highlights the potential impact of reassessment of HR and HER2 status on the surgical tumor specimen. Clinical trials that tailor adjuvant therapy recommendations based on residual biomarker analyses may further improve outcomes for women with high risk TNBC. Table. Discordance in HER2 Status Between Primary Tumor and Residual Specimen Citation Format: Alexis LeVee, Megan Wong, Sarah Flores, Nora Ruel, Heather McArthur, James Waisman, Joanne Mortimer. Receptor discordance after neoadjuvant chemotherapy with pembrolizumab in early-stage triple-negative breast cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO3-03-11.

Abstract PO2-20-09: Hiding in plain sight: A heterogeneous response in a patient with metastatic HR+/HER2- breast cancer

Abstract INTRODUCTION: Metastatic breast cancer is an infamously heterogeneous disease—characterized by a range of clinical presentations and treatment responses. In light of this heterogeneity, ASCO guidelines recommend patients with new, accessible metastatic tumors undergo a biopsy to inform treatment decisions. Here, we present a patient with HR+/HER2- disease with a long history of unusually heterogeneous responses—and a repeat metastatic biopsy that provided an answer. CASE: A 55-year-old woman presented for consultation of treatment-refractory metastatic breast cancer. She was originally diagnosed with a right-sided Stage III HR+/HER2- invasive ductal carcinoma (IDC) at the age of 33. Upon staging, she was incidentally found to have a right lower-lobe lung carcinoid tumor that was removed by lobectomy. She underwent a partial mastectomy, axillary lymph node dissection, followed by adjuvant chemo- and radiation therapy. She tolerated one week of tamoxifen which was discontinued due to adverse effects. Fifteen years later, screening mammography revealed a suspicious lesion in the right breast—biopsy consistent with a new IDC. She underwent bilateral mastectomies which showed a pT1cNxM0 G2 IDC with associated DCIS (ER+/PR+/HER2 IHC 2+, FISH-negative, Oncotype RS 12). Genetic testing was negative. The patient trialed adjuvant tamoxifen, which was discontinued due to repeat adverse effects. Two years later, rising tumor markers prompted restaging scans that demonstrated an enlarging liver lesion. Liver biopsy was consistent with metastatic adenocarcinoma of the breast (ER+/PR+/HER2 IHC 0), GATA3 positive. Patient was started on letrozole with lupron and palbociclib with disease control for two years until progression in the bone, prompting a switch of letrozole to fulvestrant with continued palbociclib. Her disease was stable for two additional years until progression of multiple liver lesions. She was then started on single-agent paclitaxel. At this point, she was seen in our office for consultation and next-line therapy options. Repeat staging scans showed heterogeneous response in the liver with overall progression. ctDNA testing revealed a mutation in MEN1 (p.Q354*, 2.8% VAF) without other actionable alterations. Patient opted to enroll into a clinical trial of an experimental ER-antagonist but experienced progression of her liver lesions on first staging scans. A second liver biopsy was performed on a progressive lesion which showed ER-/PR-/HER2- disease. She opted to enroll into a Phase 1b/2 trial with sacituzumab govitecan-hziy in combination with a PARPi. Staging scans again showed a mixed response in the liver. Given a history of mixed responses and discordant receptor staining, the differential diagnosis included loss of hormone receptor expression in the breast carcinoma versus metastases from an occult neoplasm. Additional immunohistochemical studies were performed on a subsequent liver biopsy showing positivity for chromogranin, synaptophysin, and INSM1, and negative results for ER, PR, GATA3, and TRPS1. Next-generation sequencing of the progressive lesion revealed a MEN1 SNV (p.Q354*, VAF 82%) as well as loss of 11q (MEN1 locus) suggestive of biallelic loss of MEN1—providing molecular evidence of a metastatic carcinoid tumor. A history of mixed response in the liver was concluded to be two coexisting neoplasms—a metastatic HR+/HER2- breast cancer as well as a late recurrence of a right-lower lobe carcinoid tumor from 22 years prior. DISCUSSION: The unanticipated discovery of an occult, coexisting neoplasm in the setting of a metastatic HR+/HER2- breast cancer illustrates the value of meticulous pathological review, repeat molecular testing and the use of next-generation diagnostic tools such as tumor sequencing in the advanced setting—particularly when a clinical story defies conventional expectations—to personalize care and optimize oncologic management in the face of complex biology. Citation Format: Nolan Priedigkeit, Jane Brock, Olivia Cunningham, Molly Skeffington, Melissa Hughes, Nancy Lin, Susan Lester, Heather Parsons. Hiding in plain sight: A heterogeneous response in a patient with metastatic HR+/HER2- breast cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO2-20-09.

O257: A Transcriptome Analysis of Primary Breast Cancer with Discordant Brain Metastasis Subtype

Abstract Introduction Brain metastasis (BM) occurs in 15-30% of breast cancer (BC) cases. In the era of personalised medicine, knowledge of the BM subtype is of increasing importance. However, there is often discordance between breast primary (BP) subtype and its BM. Improvements in stereotactic radiosurgery and neuroradiology have greatly reduced the number patients undergoing surgical resection. Therefore, identifying BM subtype poses a therapeutic challenge. Methods This study included 116 patients with breast cancer brain metastasis on CTRIAL-IE 09/07. Clinical subtype was evaluated using immunohistochemistry (IHC) results for oestrogen receptor (ER), progesterone receptor (PR) and HER2. 63 BP RNA sequencing (RNA-Seq) samples were analysed to identify differentially expressed genes in ER positive (ER+) primaries that subsequently lost ER in BM vs. ER+ primaries that retained ER. Results 34 (29.3%) of BPs were ER+/HER2- vs. 19 (16.4%) brain metastases, 50 (43.1%) BPs were HER2+ vs. 60 (51.7%) metastases, 32 (27.6%) BPs were TNBC vs. 37 (31.9%) metastases. The most common receptor switches were loss of ER 20/62 (32.36%), loss of PR 17/30 (56.7%) and gain of HER2 11/65 (16.9%). RNA-Seq differential expression analysis of ER+ primary/ER- BM vs. ER+ primary/ER+ BM found ALB, CPA1, GOLGA8G were significantly underexpressed in patients that subsequently lost ER, conversely MUC2, AREG and HSPB1 were significantly overexpressed. Conclusion This study profiles receptor discordance between primary BC and its matched BM. Future studies of differentially expressed genes at a transcript level may predict BM subtype using primary RNA-Seq data and allow for a more tailored treatment approach.

Receptor discordance after nipple-sparing mastectomy

BackgroundRecent studies have shown that receptor status of breast cancer change between primary tumor and recurrence, which may influence treatment strategy and prognosis, but there are few reports on receptor discordance between primary tumors and local recurrence (LR) after nipple-sparing mastectomy (NSM). Patients and methodsWe collected 74 patients who had LR after NSM for newly diagnosed stages 0 to 3 breast cancer between 2008 and 2016 at 14 institutions. We classified into 4 subtypes based on hormone receptor (HR) and human epidermal growth factor receptor 2 (HER2). We evaluated clinicopathological factors that correlate with receptor discordance and assessed the impact of receptor discordance on survival. ResultsDiscordance rates in estrogen receptor (ER), progesterone receptor (PgR) and HER2 were 9.5, 10.8 and 5.4 %, respectively. The most common change was from HR-/HER2+ to HR+/HER2+, and this pattern of receptor change occurred only in patients with nipple–areolar recurrence. Non-invasive tumors in LR, nipple–areolar recurrence (NAR), HR-/HER2+ primary tumor subtype, and the presence of chemotherapy for primary tumors were significantly associated with receptor discordance. With a median follow-up of 44.5 months (4–153 months), patients in the receptor-discordant group had no disease-free survival (DFS) event after LR resection (5-year DFS; 100 % in the receptor-discordant group vs 85.1 % in the receptor-concordant group; p = 0.2). ConclusionOur study demonstrates that the presence of chemotherapy for primary tumors, nipple-areolar recurrence, and its related factors (non-invasive tumor in LR, HR-/HER2+ primary tumor subtype) were associated with receptor discordance. However, further studies with longer follow-up periods and larger sample sizes are needed.

Incidence of HER2-expressing brain metastases in patients with HER2-null breast cancer: a matched case analysis

The HER2-directed antibody-drug conjugate trastuzumab deruxtecan is active against lower levels of HER2 expression than prior-generation therapies. The rate of HER2 expression in brain metastases among patients with initially HER2-null breast cancer is undefined, and receptor discordance in advanced breast cancer with brain metastases may underestimate CNS response potential in the absence of brain metastasis sampling. In this cohort study including 136 patients with 401 samples scored according to ASCO/CAP guidelines, 15/28 patients (54%) with HER2-null primary breast cancer have detectable HER2 expression in subsequently resected brain metastases, a significant discordant population.

Synchronous Bilateral Breast Cancer With Discordant Receptor Status: Treating One Patient but Two Diseases

The expression of hormone receptors (estrogen and progesterone) and human epidermal growth factor receptor-2 (HER2) has been used for both therapeutic and prognostic purposes in the management of breast cancer. The presence of a discordant receptor status complicates the approach to treatment in patients with synchronous bilateral breast cancer. We describe the case of a 45-year-old female with synchronous bilateral breast cancer with a triple-negative tumor and a contralateral HER2-positive tumor and discussed the impact of this on the approach to therapeutic management.

Receptor discordance among primary tumors, brain metastasesand extra-brain metastases in patients with breast cancer.

Background: To investigate the expression status of estrogen receptor(ER), progesterone receptor (PR)and HER2 in patients with breast cancer brain metastases (BM). Methods: Patients who underwent craniotomy for BM were included. The status of ER, PRand HER2 (including HER2-low expression) in primary breast tumors (PT), BM and extra-BM (EM) was determined. Results: Between PT and BM, conversion of hormone receptor and HER2 occurred in 28% (30/107) and 12% (10/86) of cases. When considering three-tiered categorization of HER2, the conversion rate reached 31%. In the paired EM and BM (n=39), the discordance rates were 18%, 3% and 22%, respectively. Conclusion: Receptor discordance was dynamic and relevant, especially using new HER2 categorization.

Incidence and prognostic significance of receptor discordance between primary breast cancer and paired bone metastases.

ER, PgR and HER-2 status are the cornerstones of choosing systemic therapy for breast cancer, but can change during the disease course. Guidelines recommended the biopsy of the metastatic tumor to reassess receptor status. Bone is the most frequent metastatic site of breast cancer but remained technically difficult to biopsy. Our study aimed to evaluate the incidence and prognostic significance of receptor discordance between primary breast cancer and paired bone metastases. One hundred and fifty-five breast cancer patients were diagnosed with pathology-confirmed bone metastasis at Fudan University Shanghai Cancer Center. Ninety-three patients with receptor status available on both primary tumor and bone metastases were included in our study. ER, PgR and HER-2 status converted from positive to negative in 10.8% (10/93), 28.0% (26/93) and 8.6% (8/93) of the patients, while ER, PgR and HER-2 status converted from negative to positive in 3.2% (3/93), 4.3% (4/93) and 1.1% (1/93) of the patients, respectively. 40.4% (17/42) of the HER2-0 tumors converted to HER2-low, which enabled them to receive the treatment of new antibody-drug conjugates (ADCs). Prior endocrine and anti-HER2 therapy were the independent risk factors for receptor conversion. Loss of HR expression in bone metastases was significantly associated with worse first-line PFS (adjusted hazard ratio=3.271, P-value=.039) and OS (adjusted hazard ratio=6.09, P-value=.011). In conclusion, our study confirmed that patients may experience receptor conversion between primary breast cancer and bone metastases, possibly influenced by prior treatments, which significantly influenced prognosis. The rebiopsy of bone metastases in patients with primary HER2-0 tumors may benefit from the new ADC drugs.

Outcome of Breast Carcinoma between ER, PR with HER-2/Neu Positive Receptor Status

Background: The most frequent kind of cancer among women is breast cancer. Evidence shows that the receptor profile of primary and metastatic breast cancer tissue differs. Archival-paired pathology samples were evaluated to determine the level of hormone receptor discordance. Objective: To evaluate the efficacy of the most frequently used biological indicators in breast cancer for predicting how well a patient would respond to surgical management and their outcome. Materials and Methods: This comparative Study was conducted in the surgery department, Rajshahi Medical College, Bangladesh, with a Matricentred base Study from January 2019 to December 2021. They also included patients (n=100) for whom tissue from either the main or secondary metastatic location was detectable. Cancers were compared and analyzed for their ER, PR, and Her-2/neu status in both the primary and the metastatic. Results: The discordance rate for ER was 17.7% (2-sided p=0.0039), with 9.7% of tumors changing from ER-positive to ER-negative and 8.0% changing from ER-negative to ER-positive. The discordance rate for PR was 37.3% (2-sided p&lt;0.0001), with Each and every one of these tumors going through a transition from PR-positive to PR-negative. As far as Her-2/neu is concerned, no major discrepancies were discovered. Conclusions: Hormone receptor status is significantly different between primary and metastatic breast cancer samples, as suggested by this dataset. Common instances of PR decline were observed. More than half of the patients had a positive hormone status, and it was found that the illness had spread to other organs in most of these cases.

Factors influencing HER2 discordance in nonmetastatic breast cancer and the role of neoadjuvant therapy.

Objective: The rates of and the factors influencing HER2 discordance in patients receiving neoadjuvant therapy for breast cancer are investigated. Methods: This study retrospectively examines the rates of HER2 and hormone receptor discordance between the biopsy and postoperative resection specimens of 400 female early-stage breast cancer patients. Results: 133 (33.3%) patients had received neoadjuvant therapy. The rate of HER2 discordance between biopsy and resection specimens was 1.7% in the control group and 5.3% in the neoadjuvant therapy group (p=0.018). The rate of HER2 discordance was higher in younger patients and in patients with T1 tumors in the neoadjuvant therapy group. Conclusion: Neoadjuvant therapy, age <40years and smaller tumor size were independent risk factors for HER2 discordance.

Radiomic Signatures for Predicting Receptor Status in Breast Cancer Brain Metastases.

BackgroundsA significant proportion of breast cancer patients showed receptor discordance between primary cancers and breast cancer brain metastases (BCBM), which significantly affected therapeutic decision-making. But it was not always feasible to obtain BCBM tissues. The aim of the present study was to analyze the receptor status of primary breast cancer and matched brain metastases and establish radiomic signatures to predict the receptor status of BCBM.MethodsThe receptor status of 80 matched primary breast cancers and resected brain metastases were retrospectively analyzed. Radiomic features were extracted using preoperative brain MRI (contrast-enhanced T1-weighted imaging, T2-weighted imaging, T2 fluid-attenuated inversion recovery, and combinations of these sequences) collected from 68 patients (45 and 23 for training and test sets, respectively) with BCBM excision. Using least absolute shrinkage selection operator and logistic regression model, the machine learning-based radiomic signatures were constructed to predict the estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) status of BCBM.ResultsDiscordance between the primary cancer and BCBM was found in 51.3% of patients, with 27.5%, 27.5%, and 5.0% discordance for ER, PR, and HER2, respectively. Loss of receptor expression was more common (33.8%) than gain (18.8%). The radiomic signatures built using combination sequences had the best performance in the training and test sets. The combination model yielded AUCs of 0.89, 0.88, and 0.87, classification sensitivities of 71.4%, 90%, and 87.5%, specificities of 81.2%, 76.9%, and 71.4%, and accuracies of 78.3%, 82.6%, and 82.6% for ER, PR, and HER2, respectively, in the test set.ConclusionsReceptor conversion in BCBM was common, and radiomic signatures show potential for noninvasively predicting BCBM receptor status.

Biomarker evolution after neoadjuvant systemic therapy in breast cancer.

e12615 Background: Tumor heterogeneity is one of the hallmarks of breast cancer (BC) and has major implications for treatment response and resistance. Currently, there are no specific guidelines regarding biomarker reassessment on residual tumor post-neoadjuvant systemic therapy (NAST). In this study, we compared biomarker discordance between pre- and post-NAST tumors at our institution and determined if actionable changes were observed. We also report the impact of the detected biomarkers differences on the choice of adjuvant treatment. Methods: We conducted a retrospective review of BC patients who received NAST followed by definitive surgery from 2004 to 2020. The initial tissue biopsies were tested for estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) status per ASCO/CAP guidelines and repeated on the residual tumor tissue after NAST. Descriptive statistics was used to compare clinicopathologic characteristics. The biomarkers were compared using Wilcoxon’s t test and McNemar’s test. Concordance analysis of intrinsic subtypes was evaluated by Cohen’s kappa method. Results: Out of 434 patients who undergone surgical resection following NAST, 95 (22%) patients were identified to have repeat biomarker testing of residual invasive BC post NAST. 30 out of the 96 patients were found to discordant receptor status on repeat biomarker testing. In this cohort of thirty patients with discordant biomarkers, median age was 51.5 (29-70 years), 33.3% cases had stage II, and 56.7% had stage III BC. 66.75 patients were ER positive and/or PR positive, 20% patients were HER2 positive with one triple positive, and 13.3% patients were triple negative on pre-NAST tumors. Majority of the retesting was performed on breast tissue (90%, n = 27). The biomarker change was noted in 11 out of 30 (36.7%) for ER, 12 out of 30 (40%) for PR, and 13 out of 30 (43.3%) for HER2 marker. Concordance analysis demonstrated that HER2 was the most prone to change (Cohen K = -0.003) from pre-NAST to post-NAST specimen, whereas ER (Cohen k = 0.26) and PR (Cohen k = 0.18) were less subject to change. Kappa assumes theoretical maximum value of 1 when pre- and post-NAST are in agreement, a negative value indicates a poor concordance. One third of patients with discordant biomarkers had additional adjuvant treatment. 8 out of 30 patients (26.7%) were started on adjuvant anti-HER2 therapy due to HER2 positivity on post-NAST tumors. After ER positivity was detected on residual BC tumors, 2 initial triple negative patients (6.7%) were initiated on adjuvant endocrine therapy. Conclusions: Biomarker discordance due to tumor heterogeneity is an increasingly recognized phenomenon. Given the prognostic and therapeutic implications of biomarker driven BC management, retesting biomarkers routinely after NAST on residual invasive tumor would be beneficial in this patient population.

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.

A DESCRIPTIVE OBSERVATIONAL STUDY OF DIFFERENCE OF ESTROGEN &amp; PROGESTERONE RECEPTOR STATUS BEFORE AND AFTER NEOADJUVANT CHEMOTHERAPY IN BREAST CANCER

Background: Neoadjuvant chemotherapy (NACT) forms the initial modality of treatment for primarily inoperable locally advanced breast cancer (LABC). A change in hormone receptor status after NACT has important therapeutic and prognostic consequences. The primary objective of this study is to compare Hormone Receptor status before and after neoadjuvant chemotherapy (discordance). The secondary objective is to study correlation between tumour response and hormone receptor expression. Method: This is a descriptive study of 80 LABC patients who received NACT. All patients who underwent core biopsy and ER/PR assessment before and after NACT were included in this study. Data was collected prospectively from each patient in a structured proforma Results and conclusion: The hormone receptor discordance rate &amp; response to NACT was assessed. ER discordance is 16.4%. in 07 patients estrogen receptor(ER) change positive to negative and in 04patients estrogen receptor change negative to positive. PR discordance is 22.4%. In 12 patients Progesterone receptor (PR) change positive to negative and in 03patients progesterone receptor change negative to positive.

The initial hormone receptor/HER2 subtype is the main determinator of subtype discordance in advanced breast cancer: a study of the SONABRE registry

PurposeThe hormone receptor (HR) and human epidermal growth factor receptor 2 (HER2) are the main parameters in guiding systemic treatment choices in breast cancer, but can change during the disease course. This study aims to evaluate the biopsy rate and receptor subtype discordance rate in patients diagnosed with advanced breast cancer (ABC).MethodsPatients diagnosed with ABC in seven hospitals in 2007–2018 were selected from the SOutheast Netherlands Advanced BREast cancer (SONABRE) registry. Multivariable logistic regression analyses were performed to identify factors influencing biopsy and discordance rates.ResultsOverall, 60% of 2854 patients had a biopsy of a metastatic site at diagnosis. One of the factors associated with a reduced biopsy rate was the HR + /HER2 + primary tumor subtype (versus HR + /HER2- subtype: OR = 0.68; 95% CI: 0.51–0.90). Among the 748 patients with a biopsy of the primary tumor and a metastatic site, the overall receptor discordance rate was 18%. This was the highest for the HR + /HER2 + primary tumor subtype, with 55%. In 624 patients with metachronous metastases, the HR + /HER2 + subtype remained the only predictor significantly related to a higher discordance rate, irrespective of prior (neo-)adjuvant therapies (OR = 7.49; 95% CI: 3.69–15.20).ConclusionThe HR + /HER2 + subtype has the highest discordance rate, but the lowest biopsy rate of all four receptor subtypes. Prior systemic therapy was not independently related to subtype discordance. This study highlights the importance of obtaining a biopsy of metastatic disease, especially in the HR + /HER2 + subtype to determine the most optimal treatment strategy.

Molecular features evaluation of metastatic foci as the basis for metastatic breast cancer treatment personalization. Is there a place of CDK4/6-inhibitors in late-line therapy after chemotherapeutic regimens?

The problem of metastatic breast cancer treatment is linked with clonal selection both in the process of tumor evolution and under the influence of previous treatment. The analysis of metastatic niche microenvironment and the molecular genetic features become essential for treatment individualization. Studies demonstrate hormonal expression and epidermal growth factor receptor (HER2neu) discordance between the primary tumor and the metastatic focus. The advantages of combined hormone therapy (CНT) with CDK4/6 inhibitors were revealed in comparison with hormone therapy (НT) with survival rates benefits in the 1st and 2nd lines of НT, as well as after the 1st line of chemotherapy in clinical trials. However, there are lack of data on patients with multiple lines of chemotherapy. In the present retrospective study, more than half of the patients were treated palliative chemotherapy before administration of CDK4/6 inhibitors. Main metastatic foci represented luminal types after biopsy, however, loss of progesterone receptor expression was noted with the initial luminal A-subtype. At the time of the data cut-off, most patients have a longterm clinical effect, improvement conditions and reduction of pain, including the cases of late line CHT setting after chemotherapeutic regimens. Taking into account the heterogeneity of metastatic breast cancer, clonal selection and phenotype discordance there is the crucial need for molecular and genetic characteristics of the metastatic process. At the same time it is possible to consider the appointment of combined hormone therapy with CDK4/6 inhibitors as additional option for late-line treatment of the disseminated process. Prospective studies on combined hormonal therapy with CDK4/6 inhibitors in metastatic breast cancer in late lines of therapy with proven HR+HER2neu-negative receptor status of the metastatic focus are strongly recommended.

Systematic review and meta-analysis of lung cancer brain metastasis and primary tumor receptor expression discordance

BackgroundTreatment paradigms for metastatic non-small cell lung cancer are increasingly based on biomarker-driven therapies, with the most common alteration being mutation in the epidermal growth factor receptor (EGFR). Change in expression of such biomarkers could have a profound impact on the choice and efficacy of a selected targeted therapeutic, and hence the objective of this study was to analyze discordance in EGFR status in patients with lung cancer brain metastasis (LCBM).MethodsUsing PRISMA guidelines, a systematic review was performed of series in the Medline database of biopsied or resected LCBM published before May, 2020. Key words included “lung cancer” and “brain metastasis” combined with “epidermal growth factor receptor/EGFR,” and “receptor conversion/discordance or concordance.” Weighted random effects models were used to calculate pooled estimates.ResultsWe identified 501 patients from 19 full-text articles for inclusion in this study. All patients underwent biopsy or resection of at least one intracranial lesion to compare to the primary tumor. On primary/LCBM comparison, the weighted pooled estimate for overall EGFR receptor discordance was 10% (95% CI 5–17%). The weighted effects model estimated a gain of an EGFR mutation in a brain metastases in patients with negative primary tumors was 7% (95% CI 4–12%). Alternatively, the weighted effects model estimate of loss of an EGFR mutation in patients with detected mutations in the primary tumor was also 7% (95% CI 4–10%). KRAS testing was also performed on both primary tumors and LCBM in a subset of 148 patients. The weighted effects estimate of KRAS-mutation discordance among LCBM compared to primary tumors was 13% (95% CI 5–27%). The weighted effects estimated of KRAS gain and loss in LCBM was 10% (95% CI 6–18%) and 8% (95% CI 4–15%), respectively. Meta-regression analysis did not find any association with any factors that could be associated with discordances.ConclusionsEGFR and KRAS mutation status discordance between primary tumor and LCBM occurs in approximately 10% and 13% of patients, respectively. Evaluation of LCBM receptor status is key to biomarker-driven targeted therapy for intracranial disease and awareness of subtype switching is critical for those patients treated with systemic therapy alone for intracranial disease.

OTHR-07. Systematic Review and Meta-analysis of Lung Cancer Brain Metastasis and Primary Tumor PD-L1 Expression Discordance

BackgroundNovel immunotherapeutic strategies, such as those targeting the PD-1/PD-L1 axis, are promising in patients with metastatic lung cancer and are often administered when tumors show PD-L1 positivity. The objective of this study was to analyze PD-L1 receptor discordance in tumor cell between the primary tumor and lung cancer brain metastasis (LCBM).MethodsA systematic review of series published prior to April 2021 obtained from the Medline database of biopsied or resected LCBM evaluating PD-L1 discordance was performed using PRISMA guidelines. Weighted random effects models were used to calculate pooled estimates.ResultsSix full-text articles (n=247 patients) with a median of 32 patients in each study (range: 24–73 patients) reported PD-L1 receptor expression analyses of both primary lung tumors and brain metastases. The majority of patients (81%) were smokers, with 67% non-small cell lung cancer and 33% small cell lung cancer. The pooled estimate for overall PD-LI receptor concordance between primary and LCBM was 76% (95% CI: 52%-90). The positivity rate varied when analyzed by various cutoff levels of PD-L1 expression; for <1% expression, it was 41% (95% CI: 22%-62%) for primary vs. 58% (95% CI: 35%-78%) for LCBM; for PD-L1 expression of 1–50%, it was 24% (95% CI: 13%-40%) vs. 19% (95% CI: 10%-33%); and for PD-L1 >50% it was 12% (95% CI: 4%-33%) vs. 21% (95% CI: 14%-29%) (p=0.425). The pooled estimate for overall PD-LI receptor discordance between primary and LCBM was 17% (95% CI: 10%-27%). Meta-regression analysis showed that age, sex, smoking status, and histology were not associated with PD-LI receptor discordance.ConclusionsPD-L1 status discordance in tumor cell occurs in approximately 20% of LCBM, with the greatest discordance in the <1% expression category. Awareness of this discordance is important for the selection of immune checkpoint inhibitor therapy as well as in the analysis of patterns of failures.