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Background Brain metastases (BM) are common among HER2+ breast cancer (BC) and prognostic stratification is crucial for optimal management. BC-GPA score and subsequent refinements (modified-GPA, updated-GPA) recapitulate prognostic factors. Since none of these indexes includes extracranial disease control, we evaluated its prognostic value in HER2+ BCBM. Methods Patients diagnosed with HER2+ BCBM at Istituto Oncologico Veneto-Padova (2002–2021) and Montpellier Cancer Institute (2001–2015) were included as exploratory and validation cohorts, respectively. Extracranial disease control at BM diagnosis (no disease/stable disease/response vs. progressive disease) was evaluated. Results In the exploratory cohort of 113 patients (median OS 12.2 months), extracranial control (n = 65, 57.5%) was significantly associated with better OS at univariate (median OS 17.7 vs. 8.7 months, p = 0.005) and multivariate analysis after adjustment for BC-GPA (HR 0.61, 95% CI 0.39–0.94), modified-GPA (HR 0.64, 95% CI 0.42–0.98) and updated-GPA (HR 0.63, 95% CI 0.41–0.98). The prognostic impact of extracranial disease control (n = 66, 56.4%) was then confirmed in the validation cohort (n = 117) at univariate (median OS 20.2 vs. 9.1 months, p Conclusions Extracranial disease control provides independent prognostic information in HER2+ BCBM beyond commonly used prognostic scores.

Background: The incidence of breast cancer (BC) brain metastases (BM) is increasing as a result of both improved diagnostic techniques and longer survival due to better treatment approaches. However, the biological complexity of BCBMs is still poorly understood. We here evaluate the genomic profile of BCBMs and assess its prognostic implications. Methods: Clinical data and BM samples (FFPE) from BC patients undergoing neurosurgery (2003-2019) at three institutions were collected. Hormone receptor (HR) and HER2 status were evaluated on the BCBM. RNA extracted from BM samples was used to measure the expression of 758 BC–related genes and 18 housekeeping genes using the Breast Cancer 360 Panel on an nCounter platform (NanoString Technologies). Intrinsic molecular subtyping was determined using the previously reported PAM50 subtype predictor (Parker et al. JCO 2009). Median overall survival from neurosurgery (OS) was calculated using the Kaplan-Meier method. The correlations between expression of each gene/PAM50 signature, BC subtype and OS were studied using univariate and multivariate Cox-models. Results: Sixty-five BCBM samples were analyzed: 32% (N=21) were HR+/HER2-, 38% (N=25) HER2+ and 29% (N=19) HR-/HER2-. With a median follow-up of 33 months, no clinical variable was significantly associated with OS, despite a trend towards a shorter survival for patients with HR-/HER2- BMs, as compared to patients with HR+/HER2- and HER2+ subtypes (median OS 9.4 versus 22.1 and 20.0 months, respectively, log-rank p=NS). The intrinsic subtype distribution, as assessed by gene-expression profiling, was 37% Basal-like, 46% HER2-enriched (HER2-E), 15% Luminal B and 2% Normal-like. Non-luminal subtypes (basal-like and HER2-E) were extensively represented, both overall and in each BC subtype (52% in HR+/HER2- subgroup, 96% in HER2+ subgroup, see Table). The PAM50 basal-like signature was significantly associated with a worse OS (HR 2.7, 95% CI 1.0-7.2, p=0.045), even after correcting for BC subtype (HR 5.2, 95% CI 1.1-23.4, p=0.032). In fact, even within the subgroup of HR+/HER2- BCBMs, the PAM50 basal-like signature was strongly associated with a worse OS (HR 92.6, 95% CI 5.0-1860.1, p=0.003) and patients with basal-like HR+/HER2- BCBMs presented a median OS similar to patients with HR-/HER2- BCBMs (mOS 9.0 vs 9.4 months). We identified 36 genes whose high expression was significantly associated with a worse OS (p< 0.05) and one gene (LINC02381) whose high expression was significantly associated with better OS (p< 0.05); for 33 of these genes (BCL11A, BMP2, BNIP3, CAV1, CDH3, CDK6, CKB, CRYAB, CXCL12, EGFR, EYA4, FOXC1, FZD8, FZD9, GABRP, GAS1, GDF5, GPC4, IL6, KRT17, KRT5, KRT6B, KRT7, LAMB3, LINC02381, MYC, NOTCH1, PRKX, PSAT1, RUNX3, SNAI1, SPRY2, TTYH1), the association was confirmed even after correcting for BC subtype (p< 0.05). Conclusions: Non-luminal intrinsic subtypes are extensively represented in resected BCBMs, even if clinically classified as HR+/HER2-. Our data suggest that basal-like genomic features might be enriched in BCBMs and might be associated with worse survival. Distribution of PAM50 intrisic subtyping on the 65 brain metastases evaluated according to hormone receptor (HR) and HER2 status Citation Format: Gaia Griguolo, Maria Vittoria Dieci, Susan Fineberg, claudia Pinato, Michele Bottosso, Luc Bauchet, Federica Miglietta, Jack Jacob, Giovanni Zarrilli, Valérie Rigau, Maria Cristina Guarascio, Francesca Zanconato, Francesca Schiavi, Matteo Fassan, William Jacot, Stefano Piccolo, Amelie Darlix, Valentina Guarneri. Gene Expression Profiling of Breast Cancer Brain Metastasis shows enrichment for non-luminal subtypes with potential prognostic implications [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr PD7-08.

Background Despite potential clinical implications, the complexity of breast cancer (BC) brain metastases (BM) immune microenvironment is poorly understood. Through multiplex immunofluorescence, we here describe the main features of BCBM immune microenvironment (density and spatial distribution) and evaluate its prognostic impact. Methods Sixty BCBM from patients undergoing neurosurgery at three institutions (2003-2018) were comprehensively assessed using two multiplex immunofluorescence panels (CD4, CD8, Granzyme B, FoxP3, CD68, pan-cytokeratin, DAPI; CD3, PD-1, PD-L1, LAG-3, TIM-3, CD163, pan-cytokeratin, DAPI). The prognostic impact of immune subpopulations and cell-to-cell spatial interactions was evaluated. Results Subtype-related differences in BCBM immune microenvironment and its prognostic impact were observed. While in HR−/HER2− BM and HER2+ BM, higher densities of intra-tumoral CD8+ lymphocytes were associated with significantly longer OS (HR 0.16 and 0.20, respectively), in HR+/HER2− BCBMs a higher CD4+FoxP3+/CD8+ cell ratio in the stroma was associated with worse OS (HR 5.4). Moreover, a higher density of intra-tumoral CD163+ M2-polarized microglia/macrophages in BCBMs was significantly associated with worse OS in HR−/HER2− and HR+/HER2− BCBMs (HR 6.56 and 4.68, respectively), but not in HER2+ BCBMs. In HER2+ BCBMs, multiplex immunofluorescence highlighted a negative prognostic role of PD-1/PD-L1 interaction: patients with a higher percentage of PD-L1+ cells spatially interacting with (within a 20 µm radius) PD-1+ cells presented a significantly worse OS (HR 4.60). Conclusions Our results highlight subtype-related differences in BCBM immune microenvironment and identify two potential therapeutic targets, M2 microglia/macrophage polarization in HER2− and PD-1/PD-L1 interaction in HER2+ BCBMs, which warrant future exploration in clinical trials.

Background: Although 1% is recommended by guidelines as cut-off for estrogen receptor (ER) positivity, the 10% cut-off is often used in clinical practice based on studies showing that breast cancers with ER ≥1% & DFS and OS Hazard Ratios for ER≥1%& Citation Format: Gaia Griguolo, Maria Vittoria Dieci, Michele Bottosso, Vassilena Tsvetkova, Carlo Alberto Giorgi, Silvia Angelini, Giulia Tasca, Enrico Cumerlato, Marcello Lo Mele, PierFranco Conte, Valentina Guarneri. Impact of estrogen receptor levels on outcome in triple negative breast cancer patients treated with (neo)adjuvant chemotherapy [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 P3-08-05.

In patients with human epidermal growth factor receptor 2 positive (HER2+) breast cancer, leptomeningeal metastases (LM) are a rare but often a fatal clinical scenario. In this multicentric study, clinical and pathologic characteristics of patients with HER2+ breast cancer developing LM were described, as well as survival outcomes. Data were gathered retrospectively from medical records of 82 patients with advanced HER2+ breast cancer and LM treated between August 2005 and July 2020. Following LM diagnosis, 79 (96.3%) patients received at least one line of anti-HER2 therapy, 25 (30.5%) patients received intrathecal therapy and 58 (70.7%) patients received radiotherapy. Overall survival (OS) was 8.3 months (95% confidence interval [CI] 5.7-11), 1-year OS was 42%, and 2-year OS was 21%. At univariate analysis, patients who were treated after 2010, had better Karnofsky performance status, were free of neurological symptoms, had better prognostic, received chemotherapy (OS difference 9.4 months, P = .024), or monoclonal antibodies (trastuzumab ± pertuzumab; OS difference 6.1 months; P = .013) after LM diagnosis, had a statistically significantly longer OS. Presence of neurological symptoms (hazard ratio 3.32, 95% CI 1.26-8.73; P = .015) and not having received radiotherapy (hazard ratio 2.02, 95% CI 1.09-3.72; P = .024) were all associated with poorer OS at multivariate analysis. To summarize, not having neurological symptoms and receiving RT at LM diagnosis were associated with prolonged OS in our cohort. Survival seemed to be prolonged with multimodality treatment, which included targeted therapy, chemotherapy, and RT to the LM sites.

The metastatic spread of breast carcinoma to the stomach is a rare event and often represents a diagnostic challenge. In the present study, 23 cases of gastric metastases from breast cancer were retrospectively identified dating back until 2007. Primitive histotype, localization, gross appearance, microscopic architecture were analyzed. Cytokeratins 7 and 20, sex hormones, HER2 and Ki67 expression was evaluated. According to the results, the series was characterized by an enrichment of lobular primitive histotype (43.7%). In most cases gastric metastases were described as parietal nodules, polypoid masses or ulcerated lesions, mainly involving the antro-angular region. In a relatively high rate (10.5%) of cases, endoscopic examinations resulted negative for macroscopic lesions. More than half of the cases (52.2%) microscopically resembled primitive poorly cohesive gastric cancer. Because gross and histological findings can be deceiving, immunohistochemistry may be essential for the diagnosis of gastric metastases from breast cancer. Accordingly with the results of our analysis and literature review, an immunohistochemical panel composed of cytokeratins 7 and 20, Estrogen and Progesteron Receptors would drastically improve diagnostic accuracy. Interaction among the clinician, endoscopist and the pathologist is also essential to provide the patient the best therapeutic option.

Background: Breast cancer (BC) is the most common tumor in women with Li-Fraumeni syndrome (LFS), with a cumulative incidence of 85% by the age of 60 years. However, LFS-related BC characteristics are still underexplored since most data derive from small retrospective cohorts. A variable enrichment in HER2-positivity (ranging from 34 to 80%) has been reported, but information regarding the response to anti-HER2 treatments are currently lacking. Moreover, data regarding the new emerging category of HER2-low are missing. Methods: Invasive BCs diagnosed in patients (pts) with TP53 germline pathogenic/likely pathogenic variant between 2002-2022 at Institut Gustave Roussy (France), Dana-Farber Cancer Institute (USA) and Hospital Sírio-Libanês (Brazil) were included. HER2 and hormone receptor (HR) expression were retrospectively retrieved from pathology records and evaluated according to ASCO/CAP recommendations in place at the time of diagnosis. HER2-positive cases were defined by an immunohistochemistry (IHC) score of 3+ and/or HER2 gene amplification by ISH; HER2-negative cases were classified as HER2-low (IHC 1+ or 2+ with negative ISH assay) or HER2-zero (IHC score 0). Pathologic complete response (pCR) was defined as ypT0/is and ypN0. Results: Among 197 invasive BCs identified in a total of 176 pts, 50.3% (n=99) were HER-positive. Among those, median age at BC diagnosis was 33 years (range 21-61) and the most frequent TP53 variants were missense mutations (n=68), affecting the DNA-binding domain in 70.6% of cases and the tetramerization domain in 29.4% of cases. Most BCs were invasive ductal carcinoma (n=90), with histologic grade 3 in 56.6% of cases. At diagnosis, most pts had early stage disease (34.3% stage I; 32.3% stage II; 21.2% stage III), while 6 pts presented de novo stage IV disease. Most tumors were HR-positive (76.8%, n=76), while 23.2% were HR-negative. 38 patients with HER2-positive BCs were treated with neoadjuvant therapy, 32 cases had post-neoadjuvant pathology reports available for pathological response classification. Among those, 26 (81.2%) were HR-positive and 6 (18.8%) HR-negative. Among pts with neoadjuvant treatment data, 87.1% received trastuzumab, which was combined with pertuzumab in 43.3% of cases; chemotherapy regimens included taxanes in all pts, anthracycline in 43.3% and platinum in 16.7%. 71.9% (n=23) of pts reached a pCR (69.2% among HR-positive and 83.3% among HR-negative), while 9 (28.1%) had residual disease; pCR rate was 82.4% among pts treated with an anthracycline-free regimen. At a median follow-up of 36 months, only one patient relapsed. Among HER2-negative BCs with available IHC score and ISH for HER2-low classification (n=85), 28 (32.9%) were HER2-low and 57 (67.1%) HER2-zero. Conclusions: In this first report of treatment results in BC pts with LFS, enrichment of HER2-positive BCs was confirmed and a remarkable pCR rate was observed with neoadjuvant treatment. Our findings require validation in a larger cohort, which is in progress. Collaborative efforts are essential for high quality data about BC treatment in this subgroup of pts. Citation Format: Michele Bottosso, Renata Lazari Sandoval, Benjamin Verret, Natalia Polidorio, Olivier Caron, Alessandra Gennari, Brittany Bychkovsky, Sophie Hyman, Maria Isabel Achatz, Valentina Guarneri, Fabrice Andre, Judy Garbe. HER2 status and response to neoadjuvant anti-HER2 treatment among patients with breast cancer and Li-Fraumeni syndrome [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P5-02-18.

Metastatic breast cancer represents an incurable condition, however, the increasing interest towards the oligometastatic entity is now challenging this assumption. Up to 20% of patients with metastatic breast cancer present with oligometastatic disease, which refers to metastatic breast cancer presenting or recurring with limited metastatic burden. In the last years, progressive advancements in imaging techniques, the growing availability of minimally invasive locoregional treatments, alongside the increasing expectations from a patient perspective, have contributed to rising the awareness towards this emerging entity. In the present work we comprehensively reviewed available evidence regarding oligometastatic breast cancer, focusing on clinical and biological notions virtually supporting the adoption of a curative approach when treating this condition. We also discussed main areas of uncertainties, providing a research agenda that may guide and fine-tune the future investigation in this field.

About a half of HER2-negative breast cancer (BC) show HER2-low expression that can be targeted by new antibody-drug conjugates. The main aim of this study is to describe the evolution of HER2 expression from primary BC to relapse by including HER2-low category in both primary and recurrent BC samples. Patients with matched primary and relapse BC samples were included. HER2 was evaluated according to ASCO/CAP recommendations in place at the time of diagnosis. A cutoff of10% cells staining for HER2-positivity was applied. HER2-negative cases were sub-classified as HER2-low (IHC = 1 + /2+ and ISH not amplified), or HER2-0 (IHC-0). 547 patients were included. The proportion of HER2-low cases was 34.2% on the primary tumor and 37.3% on the relapse samples. Among HER2-negative cases, HER2-low status was more frequent in HR-positive vs triple-negative tumors (47.3% vs 35.4% on primary tumor samples, 53.8% vs 36.2% on relapse samples). The overall rate of HER2 discordance was 38.0%, mostly represented by HER2-0 switching to HER2-low (15%) and HER2-low switching to HER2-0 (14%). Among patients with a primary HER2-negative tumor, the rate of HER2 discordance was higher in HR-positive/HER2-negative vs triple-negative cases (45.5% vs 36.7% p = 0.170). This difference was mostly driven by cases switching from HER2-0 to HER2-low. HER2-low expression is highly unstable during disease evolution. Relapse biopsy in case of a primary HER2-0 tumor may open new therapeutic opportunities in a relevant proportion of patients.

The past decade was marked by several important studies deciphering the molecular landscape of metastatic breast cancer. Although the initial goal of these studies was to find driver oncogenic events to explain cancer progression and metastatic spreading, they have also permitted the identification of several molecular alterations associated with treatment response or resistance. Herein, we review validated (PI3KCA, ESR1, MSI, NTRK translocation) and emergent molecular biomarkers (ERBB2, AKT, PTEN, HRR gene, CD274 amplification RB1, NF1, mutational process) in metastatic breast cancer, on the bases of the largest molecular profiling studies. These biomarkers will be classed according the level of evidence and, if possible, the ESCAT (ESMO) classification. Finally, we will provide some perspective on development in clinical practice for the main biomarkers.

About a half of HER2-negative breast cancer (BC) show HER2-low expression that can be targeted by new antibody-drug conjugates. The main aim of this study is to describe the evolution of HER2 expression from primary BC to relapse by including HER2-low category in both primary and recurrent BC samples. Patients with matched primary and relapse BC samples were included. HER2 was evaluated according to ASCO/CAP recommendations in place at the time of diagnosis. A cutoff of >10% cells staining for HER2-positivity was applied. HER2-negative cases were sub-classified as HER2-low (IHC = 1 + /2+ and ISH not amplified), or HER2-0 (IHC-0). 547 patients were included. The proportion of HER2-low cases was 34.2% on the primary tumor and 37.3% on the relapse samples. Among HER2-negative cases, HER2-low status was more frequent in HR-positive vs triple-negative tumors (47.3% vs 35.4% on primary tumor samples, 53.8% vs 36.2% on relapse samples). The overall rate of HER2 discordance was 38.0%, mostly represented by HER2-0 switching to HER2-low (15%) and HER2-low switching to HER2-0 (14%). Among patients with a primary HER2-negative tumor, the rate of HER2 discordance was higher in HR-positive/HER2-negative vs triple-negative cases (45.5% vs 36.7% p = 0.170). This difference was mostly driven by cases switching from HER2-0 to HER2-low. HER2-low expression is highly unstable during disease evolution. Relapse biopsy in case of a primary HER2-0 tumor may open new therapeutic opportunities in a relevant proportion of patients.

Although 1% is the recommended cut-off to define estrogen receptor (ER) positivity, a 10% cut-off is often used in clinical practice for therapeutic purposes. We here evaluate clinical outcomes according to ER levels in a monoinstitutional cohort of non-metastatic triple-negative breast cancer (BC) patients undergoing (neo)adjuvant chemotherapy. Clinicopathological data of 406 patients with ER

Introduction: Leptomeningeal metastasis (LM) is a severe complication of many solid tumors generally associated with dismal prognosis. Limited therapeutic options are available in this setting and assessment of response to treatment currently lacks validated tools. In 2017, the Response Assessment in Neuro-Oncology (RANO) LM Working Group proposed a standardized scorecard to aid in the evaluation of MRI findings in LM, which was revised and simplified in a subsequent 2019 version. To date, the prognostic impact of response to treatment evaluated according to these criteria has not been assessed in breast cancer (BC). In this study, we aim to validate this tool in a multicentric cohort of BC patients (pts) diagnosed with LM.Methods: Pts with LM from BC diagnosed at Istituto Oncologico Veneto (Padova, Italy) and Montpellier Regional Cancer Institute (Montpellier, France) between December 2005 and June 2018 were identified. Clinicopathological characteristics were collected from medical charts. Baseline and follow-up MRI scans were centrally reviewed by a dedicated radiologist and response assessment was evaluated according to the 2019 revised RANO LM response criteria (Le Rhun E. et al., Neuro-Oncology 2019).Results: A total of 225 pts diagnosed with BC-related LM were identified; among these, 142 had an available baseline brain MRI imaging and were included in the present study. Among these 142 pts, 78 had a positive cerebrospinal fluid (CSF) cytology and were classified as type I according to EANO-ESMO classification (41 type IA, 9 type IB, 28 type IC); for 64 pts CSF cytology was negative (N=25) or not performed (N=39), and were classified as type II (28 type IIA, 4 type IIB, 32 type IIC). At the time of last follow-up, 138 out of 142 pts had died and median overall survival (OS) from baseline MRI was 5.0 months (95% CI 3.4-6.7). Presence/absence of positive CSF cytology did not impact OS (median OS 5.3 versus 5.2 months, log-rank p=0.406). A total of 60 pts (positive/negative/not done CSF cytology: N=36/9/15) had an evaluable follow-up MRI imaging, with drop-off mainly due to deteriorating performance status or death. In this selected subgroup of pts, a longer OS was observed (median OS 15.2 months; 95% CI 9.5-21.0). Treatment administered for BC-related LM was heterogeneous and several pts received more than one treatment modality: systemic chemotherapy (N=44), endocrine therapy (N=27), HER2-targeted treatment (N=16), intrathecal chemotherapy (N=37) and radiotherapy (N=24). Response to treatment at time of first disease re-evaluation by brain MRI imaging was as follows: complete response for 2 pts, partial response for 12 pts, stable disease for 33 pts, and progression of disease for 13 pts. Response according to 2019 RANO criteria was significantly associated with OS (p=0.029, Table 1). Conclusions: Response assessment in pts with LM is challenging. In our study, the 2019 RANO revised response score was associated with OS in patients with LM from BC, thus validating these criteria in a real-world cohort. Response according to 2019 RANO LM criteriaMedian OS (months)OS 95% CI (months)Univariate Cox Hazard RatioUnivariate Cox Hazard Ratio 95% CIp-valueComplete Response31.1NE-NE0.100.01-0.780.028Partial Response16.10.0-37.40.410.17-0.970.043Stable Disease17.98.3-27.50.450.22-0.910.026Progression of Disease9.55.9-13.1Ref.Ref.Ref. Citation Format: Gaia Griguolo, Vittoria Aldegheri, Michele Bottosso, Francesca Caumo, Stéphane Pouderoux, Federica Miglietta, William Jacot, Maria Vittoria Dieci, Amélie Darlix, Valentina Guarneri. Response according to revised RANO criteria is associated with overall survival in breast cancer patients with leptomeningeal metastasis [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr PD4-01.