Outcome In HER2 Research Articles

Impact of extent of disease at presentation on oncologic outcomes according to pathologic response to neoadjuvant systemic therapy among participants of the I-SPY2 clinical trial.

594 Background: Recent analyses in HER2+ and triple negative (TN) breast cancer (BC) treated with neoadjuvant systemic therapy (NAST) suggest that extent of disease at presentation (tumor [T] size and nodal [N] involvement) influences outcomes independently of response to NAST, even in the context of pathologic complete response (pCR). Given this, we evaluated the association of clinical T and N status prior to NAST with long-term outcomes in I-SPY2. Methods: We identified patients (pts) with TN and HER2+ BC who received NAST on the I-SPY2 trial with available clinical T size and N status prior to NAST, pathologic response after NAST, and follow up for recurrence and survival. We conducted univariable and multivariable (MV) Cox proportional models for Event Free (EFS), Distant Recurrence Free (DRFS), and Overall Survival (OS) in TN and HER2+ BC according to response after NAST, adjusting for residual cancer burden (RCB) category. Results: Of 1,170 pts with TN or HER2+ BC, 1,013 were eligible (TN: 623 and HER2+: 390), after 157 pts were excluded due to missing critical variables. Median follow up was 4.4 years (range 0.3-10.2). Median age was 48 for TN and 49 for HER2+ BC. Following NAST, pCR was achieved in 277 (45%) pts with TN and 197 (51%) pts with HER2+ BC. Among pts with pCR, separate MV analyses for TN and HER2+ BC showed no independent association between clinical T and N category with EFS, DRFS or OS (p values all > 0.05). However, among pts with residual disease, clinical T category (but not clinical N status) prior to NAST retained independent prognostic information in both TN and HER2+ BC in a MV model adjusting for age, RCB class, and hormone receptor status (for HER2+ BC). Compared to cT1-2, cT3-4 stage at diagnosis was associated with worse EFS, DRFS, and OS in TNBC, and with worse EFS, DRFS (but not OS) in HER2+ BC (Table). Additionally, hormone receptor status was independently associated with outcomes in HER2+ BC with residual disease (data not shown). The 5y EFS for cT1-2 vs cT3-4 according to RCB class in TNBC were: RCB0: 94% vs 95%, RCB1: 90% vs 65%, RCB2: 74% vs 44% and RCB3: 45% vs 20%. The 5y EFS for cT1-2 vs cT3-4 according to RCB class in HER2+ were: RCB0: 95% vs 88%, RCB1: 89% vs 84%, RCB2: 85% vs 64% and RCB3: 56% vs 50%. Conclusions: Tumor size (but not N involvement) prior to NAST was independently associated with outcomes in TN and HER2+ BC with residual disease, independently of RCB class. TN and HER2+ BC achieving pCR exhibited favorable outcomes regardless of extent of disease prior to NAST. These data are consistent with prior findings of the Neobioscore contributing only in the context of residual disease. Clinical trial information: NCT01042379 . [Table: see text]

Abstract PO4-25-04: MHC Class I and II Expression, Functional Tertiary Lymphoid Structure (TLS), and Outcomes in Early-Stage HER2-Positive (HER2+) Breast Cancer in NCCTG N9831 (Alliance)

Abstract Background: Tertiary lymphoid structure (TLS) is an organized form of ectopic lymphoid aggregates (LA) with secondary lymphoid organ structure. Several studies showed that the presence of TLS associates with improved outcomes in multiple cancers when treated with immune checkpoint inhibitors. However, data is currently limited regarding TLS and outcomes in HER2+ breast cancer patients (pts) treated with adjuvant trastuzumab. Furthermore, distinguishing TLS and simple LA is challenging in standard hematoxylin and eosin (H&E) staining, particularly when the germinal center is absent. Emerging studies also showed the prognostic value of MHC expression in breast cancer but mainly in triple-negative breast cancer. In this study, we evaluated integrated pathological quantification and genomic data to assess functional TLS in association with MHC expression and outcomes in the N9831 trial. Methods: Pathological evaluation of LA in H&E slides from pts treated in Arm A (chemotherapy alone) and Arm C (chemotherapy with concurrent trastuzumab) in N9831 was performed. NanoString was used to quantify mRNA of MHC class I and II expression as well as TLS-related immune genes, including IFNG, ICOSLG, CXCL13, CXCR3, BCL6, IL21R, ICOS, PDCD1, CXCR5, CXCL9, TBX21, CD38, CXCL10, CLXCL11, IL21, CD200, CD19, MS4S1. Wilcoxon rank sum test, Chi-squared test, Kaplan-Meier method, and Cox regression model were used to evaluate the association between LA and baseline characteristics, MHC expression, and outcomes. Results: LA was evaluated in 526 pts in Arm A and 485 in Arm C. Greater number of LA was significantly associated with stromal tumor-infiltrating lymphocytes (sTILs), hormone receptor negative, and higher tumor grade, but not stage and age. Using multivariable Cox regression analysis, increasing numbers of LA were associated with improved recurrence-free survival in both arms combined (RFS, p 0.028). However, when evaluating each arm separately, LA was associated with improved RFS only in Arm A (HR 0.6, 95%CI 0.43-0.84, p 0.003) but not in Arm C (HR 0.72, 95%CI 0.47-1.1, p 0.134). We further evaluated TLS-related immune genes in 252 pts in Arm C with LA ≥ 1. As a continuous variable, higher expression of BCL6 (HR 0.61, 95%CI 0.41-0.92, p 0.019) and IL21R (HR 0.78, 95%CI 0.62-0.98, p 0.03) were associated with improved RFS in Arm C pts with LA ≥ 1. However, these genes were not significantly associated with outcomes in Arm C pts without LA with BCL6 (HR1.07, 95%CI 0.67-1.71, p 0.776) and IL21R (HR 0.96, 95%CI 0.71-1.29, p 0.775). Moreover, we evaluated differential gene expression between tumors with LA ≥ 1 with high BCL6 vs. LA 0. All MHC class I and II (HLA A, B, C, E, DQ, DM, DO, DP, and DQ) were significantly higher in tumors with LA ≥ 1 with high BCL6 (p < 0.001). Conclusion: A greater number of LA was associated with improved outcomes in pts with early-stage HER2+ breast cancer, particularly when treated with chemotherapy alone. Using histologic and genomic integration with the combination of pathological LA and TLS-related immune genes, we identified that pts with functional TLS with LA ≥ 1 and higher expression of BCL6 or IL21R had significantly improved outcomes when treated with trastuzumab. High MHC class I and II expressions are associated with the presence of functional TLS, underscoring the crucial role of antigen presentation in the generation of an effective adaptive immune response. Support: U10 CA180821, U10 CA180882, U24 CA196171, https://acknowledgments.alliancefound.org; Genentech; Clinicaltrials.gov Id: NCT00005970 Citation Format: Saranya Chumsri, Tracy Shachner, Zhuo Li, Nadine Norton, Alvaro Moreno-Aspitia, Gerardo Colon-Otero, Edith Perez, Aziza Nassar, E. Thompson, Keith Knutson. MHC Class I and II Expression, Functional Tertiary Lymphoid Structure (TLS), and Outcomes in Early-Stage HER2-Positive (HER2+) Breast Cancer in NCCTG N9831 (Alliance) [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 PO4-25-04.

Abstract PO3-17-02: Analysis of clinical benefit in the real world of HER2-positive metastatic breast cancer following the development of anti-HER2 therapeutics over the past 20 years

Abstract Analysis of clinical benefit in the real world of HER2-positive metastatic breast cancer following the development of anti-HER2 therapeutics over the past 20 years Ahrong Ham1, Sewon Lee1, Jungmin Jo1, Soo Ji Hong2, Ji Eun Lee2, Haena Lee2, Sungchan Gwark2, Jeongshin An2, Hyun Goo Kim2, Jun Woo Lee2, Joohyun Woo2, Woosung Lim2, Byung-In Moon2, Sei Hyun Ahn2, Hye Ah Lee3, Kyoung Eun Lee1 1 Division of Hematology and Oncology, Department of Internal Medicine, Ewha Womans University Mokdong hospital, Ewha Womans University College of Medicine, Seoul, Republic of Korea 2 Department of Surgery, Ewha Womans University Mokdong hospital, Ewha Womans University College of Medicine, Seoul, Republic of Korea 3 Clinical Trial Center, Ewha Womans University Mokdong hospital, Ewha Womans University College of Medicine, Seoul, Republic of Korea Purpose: Over the last two decades, treatment landscapes for human epidermal growth factor receptor 2 (HER2) positive metastatic breast cancer (MBC) have shown remarkable growth with the development of drugs targeting HER2. The standard of care for HER2+ MBC has continued to change with the ongoing development of new anti-HER2 therapies. We aimed to provide a comprehensive analysis of HER2-targeted therapies, clinical characteristics, and treatment outcomes in real-world practice of HER2+ MBC patients over the past 20 years. Methods: Patients who received palliative chemotherapy with HER2+ MBC between 2000 and 2022 were analyzed. We derived cohorts of two groups with or without anti-HER2 containing therapies. Patients receiving multiple anti-HER2 therapies throughout the entire period of treatment were further analyzed according to treatment regimen. The progression-free survival for palliative first-line (PFS1), and overall survival (OS) were compared between groups. A multivariate Cox regression model was used to investigate predictors of survival outcome in HER2+ MBC. Results: A total of 185 patients were analyzed. Median age was 49 years (IQR, 42-56 years). 47 patients (25.4%) were initially diagnosed with de novo stage IV disease. Visceral metastases were found in 95 patients (51.4%). The median PFS1 was 3.9 months (without anti-HER2 therapy) versus 15.6 months (with anti-HER2 therapy) between two groups (P< 0.001). Likewise, the median OS was significantly improved in anti-HER2 therapy group (34.0 months vs. 70.5 months, P=0.010). As a result of confirming the difference in OS according to the type of anti-HER2 therapies during the entire period of treatment by correspondence analysis, significant improvement was found when two or three types of anti-HER2 were used (without anti-HER2 vs. 2 types of anti-HER2, P=0.009; without anti-HER2 vs. 3 types of anti-HER2, P=0.010). Interestingly, when analyzed by treatment regimen, trastuzumab (H) + pertuzumab (P), HP + TDM-1, and H + TDM-1 significantly improved OS over regimens without anti-HER2 (without anti-HER2 vs. HP, P=0.009; without anti-HER2 vs. HP + TDM-1, P=0.013; without anti-HER2 vs. H + TDM-1, P=0.028, respectively). HP + TDM-1 therapies significantly improved survival rate compared to H single containing regimen (P=0.029). Based on our multiple Cox regression model, visceral metastasis was a significant poor OS prognostic factor and two and three types of anti-HER2 therapies were associated better OS prognosis (visceral metastasis: HR=2.40, P=0.003; 2 types of ant-HER2: HR=0.29, P=0.001; 3 types of anti-HER2: HR=0.22, P=0.018, respectively). Conclusions: Anti-HER2 therapies significantly improved PFS1 and OS. Continuing treatment by changing anti-HER2 therapies may act as a better prognostic factor. Further prospective studies are required. Citation Format: Ahrong Ham, Sewon Lee, Jungmin Jo, Soo Ji Hong, Ji Eun Lee, Haena Lee, Sungchan Gwark, Jeongshin An, Hyun-Goo Kim, Jun Woo Lee, Joohyun Woo, Woosung Lim, Byung-In Moon, Sei Hyun Ahn, Hye Ah Lee, Kyoung Eun Lee. Analysis of clinical benefit in the real world of HER2-positive metastatic breast cancer following the development of anti-HER2 therapeutics over the past 20 years [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 PO3-17-02.

Abstract 5230: A modified FcγRI expressing T cell (SolidT) exhibits profound anti-tumor activity followed by maturation into effector memory t cells that can be reactivated to kill a secondary tumor

Abstract We previously described a subset of cytotoxic FcγRI (CD64)-expressing T cells in tumors and inflamed tissues (PMID 31449054). We subsequently expressed an engineered modified CD64 into T cells (“SolidT”) and demonstrated that these cells possessed greater specificity for tumor over normal tissues, reduced exhaustion, and attenuated cytokine secretion compared to other engineered cell therapies. SolidT activation correlates with surface tumor antigen density enabling the differentiation between tumor cells and normal cells by use of a specific antibody targeting tumor antigens. We previously showed that SolidT + mAb has anti-tumor activity in vitro and in vivo in several tumor models, including immunodeficient HER2 xenografts and an immunocompetent syngeneic B16-TYRP1 model (PMID 37070661). In this study, we further assessed the effect of SolidT on HER2+ tumors in a rechallenge model and extended the platform to CD20+ lymphoma models by combining SolidT with rituximab. In an in vivo experiment using HER2+, NCI-N87 cells in immunodeficient mice, several mice in the SolidT + trastuzumab group experienced complete tumor clearance. These mice were monitored until day 84, then rechallenged with NCI-N87 cells along with a new control group. After tumor establishment, mice were treated only with trastuzumab weekly for two weeks. While tumors in the control group progressed, the tumors in the rechallenged mice were completely cleared with a trastuzumab boost only, suggesting a SolidT cell memory response. Bone marrow from these rechallenged mice was analyzed and revealed the presence of effector memory SolidT cells. The SolidT model was then studied in a human, CD20+ lymphoma model in vitro and in vivo in immunodeficient mice. SolidT + rituximab was more potent in-vivo against CD20+ lymphoma cells than rituximab. In vivo, mice treated with SolidT + rituximab had significantly greater survival, lower tumor burden, and fewer sites of metastases than mice treated with rituximab alone. Bone marrow from these mice was analyzed and revealed the presence of effector memory SolidT cells in mice treated with SolidT + rituximab. We demonstrated that marrow resident SolidT cells developed an effector memory phenotype that positively correlated with outcome in HER2+ and CD20+ xenograft models, consistent with earlier data from a syngeneic B16 melanoma model. We further demonstrated that SolidT cells can be reactivated in a rechallenge model with only the addition of tumor targeting mAb, resulting in the eradication of the recurring tumors. This data further confirms that the SolidT platform can be targeted against different tumor antigens by using different tumor targeting mAbs. The SolidT platform could represent a paradigm shift in the approach to engineered cellular therapy for hematological malignancies and solid tumors. Citation Format: Shahar Dotan, Noam Pilpel, Peleg Rider, Hana Shpilt, Diana Rasoulouniriana, Yaron Carmi, James E. Wooldridge. A modified FcγRI expressing T cell (SolidT) exhibits profound anti-tumor activity followed by maturation into effector memory t cells that can be reactivated to kill a secondary tumor [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5230.

Genomic Alterations Correlated to Trastuzumab Resistance and Clinical Outcomes in HER2+/HR- Breast Cancers of Patients Living in Northwestern China.

Anti-HER2 therapy has significantly improved the survival rates of patients with HER2+ breast cancer. However, a subset of these patients eventually experience treatment failure, and the underlying genetic mechanisms remain largely unexplored. This underscores the need to investigate the genomic heterogeneity of HER2+ breast cancer. In this study, we focus on HER2+/HR- breast cancer, as it differs from HER2+/HR+ breast cancer in terms of genetic and biological characteristics. We performed gene-targeted genome sequencing on 45 HER2+/HR- breast cancer samples and identified 650 mutations across 268 cancer-related genes. TP53 (71.1%) and PIK3CA (35.6%) were the most frequently mutated genes in our sample. Additionally, ERBB2 (77.8%), CDK12 (42.2%), and MYC (11.1%) exhibited a high frequency of copy number amplifications (CNAs). Comparative analysis with two other HER2+/HR- breast cancer cohorts revealed that our cohort had higher genetic variation rates in ARID1A, PKHD1, PTPN13, FANCA, SETD2, BRCA2, BLM, STAG2, FAT1, TOP2A, POLE, ATM, KMT2B, FGFR4, and EPAS1. Notably, in our cohort, NF1 and ATM mutations were more prevalent in trastuzumab-resistant patients (NF1, p=0.016; ATM, p=0.006) and were associated with primary trastuzumab resistance (NF1, p=0.042; ATM, p=0.021). Moreover, patients with NF1 mutations (p=0.009) and high histological grades (p=0.028) were more likely to experience early relapse. Ultimately, we identified a unique cancer-related gene mutation profile and a subset of genes associated with primary resistance to trastuzumab and RFS in patients with HER2+/HR- breast cancer in Northwest China. These findings could lay the groundwork for future studies aimed at elucidating the mechanisms of resistance to trastuzumab and improving HER2-targeted treatment strategies.

Luminal A Versus B After Choosing Wisely: Does Lymph Node Surgery Affect Oncologic Outcomes?

In 2016, the Choosing Wisely campaign recommended against routine sentinel lymph node biopsy (SLNB) in women ≥ 70 years old diagnosed with early-stage hormone receptor positive (HR+), HER2 negative (HER2-) breast cancer. No distinction is made between luminal A and luminal B phenotypes, despite luminal B being considered more aggressive. This study evaluates the effect of SLNB on oncologic outcomes in HER2- luminal B versus luminal A breast cancer. We performed an IRB-approved, single institution, retrospective cohort study from 2010 to 2020 of women aged ≥ 70 years with clinically node negative, HR+ breast cancer undergoing definitive surgical treatment. Luminal status was defined by gene expression panel testing, Ki67%, and/or pathologic grading. Primary endpoints included locoregional recurrence (LRR), disease free survival (DFS), and overall survival (OS). SLNB did not correlate with significant differences in LRR in luminal A (p = 0.92) or luminal B (p = 0.96) disease. SLNB correlated with improved DFS (p < 0.01) and OS (p < 0.001) in luminal A disease, but not in luminal B disease (DFS p = 0.73; OS p = 0.36). On multivariate analysis, age (HR = 1.17; p < 0.01) and tumor size (HR = 1.03; p < 0.05) were associated with DFS, while SLNB was not (p = 0.71). Luminal status (HR = 0.52, p < 0.05), age (HR = 1.15, p < 0.01), and comorbidities (HR = 1.35, p < 0.05) were associated with OS, but not SLNB (p = 0.71). Our results suggest that SLNB may be safely omitted in patients aged ≥ 70 years with luminal B disease given similar LRR in luminal A disease. Our findings suggest that DFS and OS are driven by tumor biology, patient age, and comorbidities rather than receipt of SLNB.

Real-world, single-center experience on the outcomes of neoadjuvant chemotherapy and trastuzumab alone or in combination with pertuzumab in human epidermal growth factor receptor-2 breast cancer patients.

e12589 Background: Neoadjuvant chemotherapy (NACT) is the standard of care for early-stage breast cancer (BC). Human epidermal growth factor receptor 2 (HER2) positive disease constitutes a large proportion of BC patients, and HER2 overexpression is associated with poor prognosis. The introduction of HER2+ targeted therapies, such as trastuzumab and pertuzumab, has resulted in improved outcomes in HER2+ BC. NACT in combination with HER2 targeted therapies aims at achieving pathological complete response (pCR) and an improved survival rates. Methods: We performed a retrospective review of HER2+ BC patients who were treated at Medanta – The Medicity Hospital, Gurugram, Haryana, India, between 2011 and 2021. A total of 108 HER2+ BC patients who received NACT with platinum, anthracycline or taxane-based regimens, along with trastuzumab alone or in combination with pertuzumab, were included. Results: Of 108 enrolled patients, 66 and 42 patients received neoadjuvant single-blockade (trastuzumab) and dual-blockade (trastuzumab and pertuzumab) anti-HER2 therapy, respectively. The majority of patients were aged &lt; 60 years. The patient populations were comparable in terms of clinical stage, hormone receptor status, histopathology category [Invasive ductal carcinoma (IDC) being most common] and Ki67 status for both groups. All patients had IHC3+/FISH+ HER2 expression. No significant (p = 0.896) difference was observed for breast conserving surgery between the groups. A higher pCR rate after surgery was reported in the dual-blockade versus single-blockade group (50% vs. 39.2%; p = 0.271). The median follow-up duration was 21.9 and 15.2 months in the single-blockade and dual-blockade groups, respectively. For dual- vs. single- blockade groups, the 1-year OS rates were 100% each, and 3-year OS rates were 100% vs. 98.48%. For dual- vs. single- blockade groups, the 1-year DFS rates were 100% vs. 95.45%, and 3-year DFS rates were 92.85% vs. 80.3% respectively. Conclusions: Neoadjuvant chemotherapy with dual HER2-blockade had higher pCR and survival rates compared with the single HER2-blockade strategy in HER2 positive breast cancer. [Table: see text]

A phase II study of weekly carboplatin and nab-paclitaxel with trastuzumab or bevacizumab as neoadjuvant therapy for patients with early-stage nonmetastatic breast cancer.

e12623 Background: Neo-Adjuvant chemotherapy (NAC) allows patients to undergo breast conserving surgery, treats micro metastatic disease and improves patient outcomes. Achieving a complete pathologic response to NACT has prognostic significance in HER2+ and triple negative breast cancer. Anthracyclines are commonly integrated to Neo-adjuvant regimens. Their use is limited by cardiac and hematologic toxicity. We proposed that weekly Carboplatin and Nab-Paclitaxel is a well-tolerated regimen and aim to demonstrate that this approach can be a selective anthracycline sparing regimen with comparable improvement in recurrence free survival (RFS) and pathologic complete response (pCR). Methods: We conducted a single institution, open label, prospective Phase II clinical trial for patients with non-metastatic breast cancer who were eligible to receive NACT. All Patients with stage I-III breast cancers were treated with weekly Nab-paclitaxel (90 mg/m2) and carboplatin (AUC 2) for 12 weeks. Patients with HER2+ breast cancer received trastuzumab (4 mg/kg induction, followed by 2 mg/kg/week) weekly for 12 weeks. Triple negative and HR + patients received bevacizumab (10 mg/kg) every other week for 5 doses. Results: We enrolled 125 patients from February 2008 to December 2015. 85 pts were HER2- and 42 pts were HER2+. The pCR rate was 17.6% (15 pts) in the HER2- cohort and 50% (21 pts) in the HER2+ cohort. In the subgroup analysis based on hormone receptor (HR) status, pts with HR- tumor had more favorable response with higher rate of pCR compared with pts with HR+ tumor. In the HER2- cohort, the total pCR rate was 34% in HR- tumors vs 8% in HR+ tumors, P = 0.0018. After a median follow up of 53 months, overall survival was 88.9% for pts who achieved pCR and 77.7% for those who did not. HR = 0.3664, CI = 0.06147 to 2.1843, P = 0.34.In the HER2+ cohort the pCR rate was 33% in pts with HR+ tumors vs 72% in pts with HR- tumor, P = 0.0137. After a median follow up of 53 months, overall survival was 100% for pts who achieved pCR vs 20% in those who did not. The relapse-free survival was 90% vs 25% respectively (HR = 0.0669, CI = 0.00454 to 0.9251 P = 0.0016). In the entire study population, 6 pts (4.7%) had treatment discontinuation and 12 pts (9.4%) had dose reduction due to side effects. The rate of treatment disruption was higher in the HER2- cohort. Nausea, vomiting, and neutropenia were the most common side effects in both cohorts (7.9%) followed by thrombocytopenia and anemia (4.7%). Hematologic toxicity was the most common toxicity grade 3 and 4. Conclusions: Combination of nab-paclitaxel and carboplatin plus targeted therapy as an anthracycline sparing neoadjuvant chemotherapy showed a good pCR rate in HER2+ subgroup and moderate activity in TNBC subset. High rate of pCR was associated with high survival outcomes in HER2+ cohort. The regimen was well tolerated among both cohorts. Clinical trial information: NCT00618657 .

224P Clinical features and outcomes in HER2+ mBC patients treated with trastuzumab deruxtecan: A subgroup analysis of the De-REAL study

224P Clinical features and outcomes in HER2+ mBC patients treated with trastuzumab deruxtecan: A subgroup analysis of the De-REAL study

Demographic and Clinical Features of Patients with Metastatic Breast Cancer: A Retrospective Multicenter Registry Study of the Turkish Oncology Group.

This multicenter registry study aims to analyze time-related changes in the treatment patterns and outcome of patients with metastatic breast cancer (MBC) over a ten-year period. Correlations between demographic, prognostic variables and survival outcomes were carried out in database aggregates consisting of cohorts based on disease presentation (recurrent vs. de novo) and the diagnosis date of MBC (Cohort I: patient diagnosed between January 2010 and December 2014; and Cohort II: between January 2015 and December 2019). Out of 1382 patients analyzed, 52.3% patients had recurrent disease, with an increased frequency over time (47.9% in Cohort I vs. 56.1% in Cohort II, p < 0.001). In recurrent patients, 38.4% (n = 277) relapsed within two years from initial diagnosis, among which triple-negative BC (TNBC) was the most frequent (51.7%). Median overall survival (OS) was 51.0 (48.0-55.0) months for all patients, which was similar across both cohorts. HER2+ subtype had the highest OS among subgroups (HER2+ vs. HR+ vs. TNBC; 57 vs. 52 vs. 27 months, p < 0.001), and the dnMBC group showed a better outcome than recMBC (53 vs. 47 months, p = 0.013). Despite the lack of CDK inhibitors, luminal A patients receiving endocrine therapy had a favorable outcome (70 months), constituting an appealing approach with limited resources. The only survival improvement during the timeframe was observed in HER2+ dnMBC patients (3-year OS Cohort I: 62% vs. Cohort II: 84.7%, p = 0.009). The incorporation of targeted agents within standard treatment has improved the outcome in HER2+ MBC patients over time. Nevertheless, despite advances in early diagnosis and treatment, the prognosis of patients with TNBC remains poor, highlighting the need for more effective treatment options.

Abstract P3-02-05: Interim Analysis Results from a European Disease Registry Study Aimed to Prospectively Observe Treatment Patterns and Outcomes in Patients with HER2+ Unresectable Locally Advanced or Metastatic Breast Cancer

Abstract BACKGROUND: Metastatic breast cancer (MBC) is incurable, with the primary goal of treatment being to extend survival while preserving quality of life. Treatment options available to patients (pts) with human epidermal growth factor receptor-2 positive breast cancer (HER2+ BC) may vary between countries, in terms of both the drugs used and the sequence in which they are used. There is limited data available on the clinical characteristics and outcomes in pts with unresectable locally advanced (LA) BC. This study aimed to capture real-world data on treatment patterns and clinical outcomes in HER2+ unresectable LABC and MBC. METHODS: SAMANTHA (NCT02913456) is an ongoing, prospective, multicentre non-interventional study designed to observe pts with HER2+ unresectable LABC or MBC for a period of up to 8 years on study. The primary objectives are progression-free survival (PFS), assessed according to standard medical practice, and the treatment received. Secondary objectives included overall survival (OS), duration of response and safety. This pre-planned interim analysis reports baseline characteristics, treatment regimens received, first-line (1L) PFS by advanced BC status and the incidence of adverse events (AEs). RESULTS: The study enrolled 647 pts from five European (EU) countries (Nov 2016-Nov 2019); 629 received 1L treatment and were included in data analysis. At data cut-off date (16 Nov 2021), median follow-up on study was 30.4 months (mo; range: 0.1; 60.0); 342 (54%) pts discontinued 1L treatments, of whom 170 (50%) pts received 2L treatments, 74 pts died, 49 pts were lost to follow-up, 35 pts withdrew consent and 14 pts withdrew due to physician decision. The full analysis set (FAS) included 222 (35%) LABC pts and 407 (65%) MBC pts [Table]. Pertuzumab/trastuzumab based regimens were given as 1L in the majority of pts [462 (73 %)]. The FAS Median (m) PFS in 1L was 41.3 mo (95% CI: 36.1, 54.1) for LABC and 23.5 mo (95% CI: 20.6, 27.6) for MBC. Median OS was not reached. In the FAS, any AEs were reported in 352 (56%) pts; of these 212 (34%) had a grade 3 or higher AE. Serious (S) AEs were reported in 135 (22%) pts; of whom, 36 (6%) pts had treatment related SAEs. CONCLUSIONS: This interim analysis of SAMANTHA provides a snapshot of LABC/MBC treatment practices in five EU countries, where pertuzumab/trastuzumab based regimens appear to be the most used 1L treatment options, which aligns with the recommended standard of care. The mPFS is consistent with previous literature although higher than what was reported in the pivotal clinical trial CLEOPATRA. Given the good outcome observed in 1L and the current follow-up period of 30.4 mo, the data are not yet mature enough to provide complete insights into the treatment sequencing patterns and the clinical outcomes associated with these treatments. Acknowledgments: The study is sponsored by F. Hoffmann-La Roche Ltd. Table: Demographics and baseline disease characteristics of patients by status of advanced BC Citation Format: Marija Balic, Luis Costa, Joseline Ojaimi, Cristina Marinela Oprean, José L. Passos Coelho, Isabel Pazos, Fabio Puglisi, Thibaut Sanglier, Giuseppa Scandurra, Michael Schenker, Laurentia A. Wahyudi, Georgi Zhbantov, Constanta Timcheva. Interim Analysis Results from a European Disease Registry Study Aimed to Prospectively Observe Treatment Patterns and Outcomes in Patients with HER2+ Unresectable Locally Advanced or Metastatic Breast Cancer [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 P3-02-05.

Abstract P4-07-62: Real-World, Single-Center Experience on the Outcomes of Neoadjuvant Chemotherapy and Trastuzumab alone or in Combination with Pertuzumab in Human Epidermal Growth Factor Receptor 2 Breast Cancer Patients

Abstract Background: Neoadjuvant chemotherapy is the standard of care for early stage breast cancer. Human epidermal growth factor receptor 2 (HER2) positive disease constitutes a large proportion of breast cancer patients, and HER2 overexpression is associated with poor prognosis. The induction of HER2+ targeted therapies, such as trastuzumab and pertuzumab, has resulted in improved outcomes in HER2+ breast cancers. Neoadjuvant chemotherapy in combination with HER2 targeted therapies aims at achieving pathological complete response (pCR) and an improved survival. Methods: We performed a retrospective review of HER2+ breast cancer patients who were treated at Medanta – The Medicity Hospital, Gurugram, Haryana, India, between 2011 and 2021. A total of 108 HER2+ breast cancer patients who received neoadjuvant chemotherapy with platinum, anthracycline or taxane-based regimens, along with trastuzumab alone or in combination with pertuzumab, were included. Results: Of 108 enrolled patients, 66 and 42 patients received single-blockade (trastuzumab) and dual-blockade (trastuzumab and pertuzumab) neoadjuvant anti-HER2 therapy, respectively. The majority of patients were aged &amp;lt; 60 years. The patient populations were comparable in terms of clinical stage, hormone receptor status, histopathology category (IDC being most common) and Ki67 status for single- and dual-blockade groups. All patients had IHC3+/FISH+ HER2 expression. No significant (p=0.896) difference was observed for breast conserving surgery between the groups. A higher pCR rate after surgery was reported in the dual-blockade group versus single-blockade group (50% vs. 39.2%; p=0.271). The median follow-up duration was 21.9 and 15.2 months in the single-blockade and dual-blockade groups, respectively. For dual- vs. single- blockade groups, the 1-year OS rates were 100% vs. 100%, and 3-year OS rates were 100% vs. 98.48%. For dual- vs. single- blockade groups, the 1-year DFS rates were 100% vs. 95.45%, and 3-year DFS rates were 92.85% vs. 80.3%. Conclusion: Neoadjuvant chemotherapy with dual HER2-blockade had higher pCR and survival rates compared with the single HER2-blockade strategy in HER2 positive breast cancer. Table. Patient characteristics BCS, breast conserving surgery; ER, estrogen receptor; PR, progesterone receptor; IDC, invasive ductal carcinoma; ILC, invasive lobular carcinoma. Citation Format: Ashok K. Vaid, Devender Sharma, Jyoti Wadhwa, Rajeev Agarwal, Kanchan Kaur, Shina Goyal, Dheeraj Gautam, Jyoti Arora, Sabhyata Gupta, Ashok Sen, Ruchika K. Goel, Shagun Mahajan. Real-World, Single-Center Experience on the Outcomes of Neoadjuvant Chemotherapy and Trastuzumab alone or in Combination with Pertuzumab in Human Epidermal Growth Factor Receptor 2 Breast Cancer Patients [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 P4-07-62.

Abstract P4-03-05: HER2 + Breast Cancer in Afro-Caribbean Women in New York City

Abstract Background: Human Epidermal Growth Factor receptor 2 (HER2) protein overexpression and/or amplification positive breast cancer accounts for 14% of breast cancer cases in the United States. The use of anti-HER2 targeted therapy in combination with chemotherapy has resulted in better response rates leading to better outcomes in patients with this breast cancer subtype. Few studies directly investigate breast cancer outcomes in Afro-Caribbean women in the U.S, and fewer studies have investigated HER2 positive (HER2+) disease in this patient group. We describe the clinicopathologic characteristics and outcomes of HER2+ breast cancer in this minority patient group. Methods: This is a retrospective study conducted at Kings County Hospital (KCH), a public hospital in Brooklyn, a New York City borough with the highest population of Afro-Caribbeans in the United States, outside of Miami, Florida. Data of patients diagnosed with breast cancer from 2015-2018 was collected from the hospital’s tumor registry. Clinical and pathologic data was collected and analyzed with descriptive statistics and Chi-square testing. Results: A total of 299 women with breast cancer were screened and 18% (54) had HER2+ disease. 63% (34) of these patients were post-menopausal, with median age 56. 78% self-identified as Afro-Caribbean. 19% (11) of patients reported first- or second-degree relatives with a breast cancer diagnosis, 22% (13) reported first-degree relative with non-breast malignancy. Half of the patients younger &amp;lt; 45 years age reported a positive family history of any type of cancer. 74% of patients presented with Nottingham Grade 3 disease, 31% with localized disease, without lymph node involvement, 52% with regional lymph node involvement, and 17% with distant metastasis. 63% of patients were estrogen receptor (ER) positive and 37% were ER negative. Post-menopausal women presented with higher rates of lymph node involvement at 70.4% vs. 50% in pre-menopausal women (p=0.17). 41% (22) of patients received neoadjuvant chemotherapy while 31% received adjuvant therapy with standard chemotherapy and anti-HER2 targeted treatment. Of the 22 patients who received neoadjuvant treatment, 14% had complete pathologic response, 68% had partial response, and 18% had disease progression. Treatment response to neoadjuvant therapy was independent of lymph node status (90.9% in local disease vs. 85.7% in lymph node involvement, p=0.66). The median progression free survival was 48 months, overall survival at 7 years was not reached, and mortality rate was 16.7%. Conclusions: In our analysis, Afro-Caribbean patients with HER2+ breast cancer presented with high grade tumor, high incidence of regional lymph node involvement, and ER positive tumors. Noteworthy was the presence of strong family history of cancers, suggestive of familial or inherited cancers. Pathologic complete response to neoadjuvant chemotherapy was remarkably less than anticipated, and further research is warranted to study tumor biology and responses to standard HER2 systemic therapies in these patients.

Brain metastasis as the first and only metastatic relapse site portends worse survival in patients with advanced HER2 + breast cancer.

Current systemic therapy guidelines for patients with HER2 + breast cancer brain metastases (BCBrM) diverge based on the status of extracranial disease (ECD). An in-depth understanding of the impact of ECD on outcomes in HER2 + BCBrM has never been performed. Our study explores the implications of ECD status on intracranial progression-free survival (iPFS) and overall survival (OS) after first incidence of HER2 + BCBrM and radiation. A retrospective analysis was performed of 151 patients diagnosed with initial HER2 + BCBrM who received radiation therapy to the central nervous system (CNS) at Duke between 2008 and 2021. The primary endpoint was iPFS defined as the time from first CNS radiation treatment to intracranial progression or death. OS was defined as the time from first CNS radiation or first metastatic disease to death. Systemic staging scans within 30days of initial BCBrM defined ECD status as progressive, stable/responding or none (isolated brain relapse). In this cohort, > 70% of patients had controlled ECD with either isolated brain relapse (27%) or stable/responding ECD (44%). OS from initial metastatic disease to death was markedly worse for patients with isolated intracranial relapse (median = 28.4m) compared to those with progressive or stable/responding ECD (48.8m and 71.5m, respectively, p = 0.0028). OS from first CNS radiation to death was significantly worse for patients with progressive ECD (16.9m) versus stable/responding (36.6m) or isolated intracranial relapse (28.4m, p = 0.007). iPFS did not differ statistically based on ECD status. Receipt of systemic therapy after first BCBrM significantly improved iPFS (HR 0.45, 95% CI: 0.25-0.81, p = 0.008) and OS (HR: 0.43 (95% CI: 0.23-0.81); p = 0.001). OS in patients with HER2 + isolated BCBrM was inferior to those with concurrent progressive or stable/responding ECD. Studies investigating initiation of brain-penetrable HER2-targeted therapies earlier in the disease course of isolated HER2 + intracranial relapse patients are warranted.

Abstract 5627: Functional tertiary lymphoid structure (TLS) and outcome in HER2-positive (HER2+) breast cancer in NCCTG N9831 (Alliance)

Abstract Background: Previous studies showed conflicting results regarding association between stromal tumor infiltrating lymphocytes (sTIL) and outcome in HER2+ breast cancer. While sTIL were not associated with outcome in patients (pts) treated with trastuzumab in N9831, immune functions genes are linked to outcome in these pts. TLS is an organized form of ectopic lymphoid aggregates (LA) with secondary lymphoid organ structure. Several studies showed that TLS associates with improved outcome in multiple cancers. However, distinguishing TLS and simple LA is challenging, particularly when germinal center is absent. In this study, we evaluated integrated pathological quantification and genomic data to assess functional TLS. Methods: Pathological evaluation of LA in H&amp;E slides from pts treated in Arm A (chemotherapy alone) and Arm C (chemotherapy with concurrent trastuzumab) in N9831 was performed. NanoString was used to quantify mRNA. Wilcoxon rank sum test, Chi squared test, Kaplan-Meier method and Cox regression model were used to evaluate association between LA and baseline characteristics as well as outcomes. Results: LA was quantified in 1011 pts (526 Arm A, 485 Arm C). Greater number of LA was significantly associated with higher tumor grade, ER/PR negativity and increasing sTIL, but not age, tumor size or lymph node status. Increasing numbers of LA were associated with improved RFS in both arms combined (p 0.028). However, using multivariable Cox regression analysis in each treatment arm, LA (≥ 1 vs 0) was associated with improved RFS only in Arm A (HR 0.6, 95%CI 0.43-0.84, p 0.003) but not Arm C (HR 0.72, 95%CI 0.47-1.1, p 0.134). Further evaluation of expression of TLS-related immune genes including IFNG, ICOSLG, CXCL13, CXCR3, BCL6, IL21R, ICOS, PDCD1, CXCR5, CXCL9, TBX21, CD38, CXCL10, CLXCL11, IL21, CD200 was carried out among 252 pts in Arm C with LA ≥ 1. Among these 16 TLS-related immune genes, as a continuous variable, higher expression of BCL6 (HR 0.61, 95%CI 0.41-0.92, p 0.019) and IL21R (HR 0.78, 95%CI 0.62-0.98, p 0.03) were associated with improved RFS in Arm C pts with LA ≥ 1. However, these genes were not significantly associated with outcome in Arm C pts without LA with BCL6 HR1.07 (95%CI 0.67-1.71, p 0.776) and IL21R HR 0.96 (95%CI 0.71-1.29, p 0.775). Conclusion: Similar to sTIL, greater number of LA was associated with improved outcome in HER2+ pts treated with chemotherapy alone but not chemotherapy in combination with trastuzumab. Using histogenomic integration with the combination of pathological LA and TLS-related immune genes, we identified that pts with functional TLS with LA ≥ 1 and higher expression of BCL6 or IL21R had significantly improved outcome when treated with trastuzumab. Future studies are needed to further confirm these findings. Support: U10 CA180821, U24 CA196171, https://acknowledgments.alliancefound.org; Genentech; Clinicaltrials.gov Id: NCT00005970 Citation Format: Saranya Chumsri, Tracy R. Shachner, Zhuo Li, Nadine Norton, Alvaro Moreno-Aspitia, Gerardo Colon-Otero, Edith A. Perez, E. A. Thompson, Aziza Nassar, Keith L. Knutson. Functional tertiary lymphoid structure (TLS) and outcome in HER2-positive (HER2+) breast cancer in NCCTG N9831 (Alliance) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5627.

Targeting Cell Cycle Progression in HER2+ Breast Cancer: An Emerging Treatment Opportunity.

Layman summaryHER2 is an oncogenic driver in a subset of breast cancer. Despite the fact that there are the options of several anti-HER2 targeted therapies, most patients with metastatic HER2+ breast cancer die from the disease. Therapies to overcome treatment resistance in the metastatic settings (including brain metastasis) are actively being pursued. Recently, cell cycle inhibitors (CDK 4/6 inhibitors) have been approved to manage hormone receptor-positive breast cancer, and have encountered tremendous success. The cell cycle signaling proteins, Cyclin D-CDK4/6, are downstream of HER2 and play a key role in cellular proliferation. Moreover, cell cycle inhibitors have the capacity to cross the blood–brain barrier. Here, we review the published literature with regard to the rationale for CDK4/6-directed therapies in HER2+ breast cancer.The development of HER2-targeted therapies has dramatically improved patient survival and patient management and increased the quality of life in the HER2+ breast cancer patient population. Due to the activation of compensatory pathways, patients eventually suffer from resistance to HER2-directed therapies and develop a more aggressive disease phenotype. One of these mechanisms is the crosstalk between ER and HER2 signaling, especially the CDK4/6-Cyclin D-Rb signaling axis that is commonly active and has received attention for its potential role in regulating tumor progression. CDK 4/6 inhibitors interfere with the binding of cell-cycle-dependent kinases (CDKs) with their cognate partner cyclins, and forestall the progression of the cell cycle by preventing Rb phosphorylation and E2F release that consequentially leads to cancer cell senescence. CDK 4/6 inhibitors, namely, palbociclib, ribociclib, and abemaciclib, in combination with anti-estrogen therapies, have shown impressive outcomes in hormonal receptor-positive (HR+) disease and have received approval for this disease context. As an extension of this concept, preclinical/clinical studies incorporating CDK 4/6 inhibitors with HER2-targeted drugs have been evaluated and have shown potency in limiting tumor progression, restoring therapeutic sensitivity, and may improving the management of the disease. Currently, several clinical trials are examining the synergistic effects of CDK 4/6 inhibitors with optimized HER2-directed therapies for the (ER+/-) HER2+ population in the metastatic setting. In this review, we aim to interrogate the burden of HER2+ disease in light of recent treatment progress in the field and examine the clinical benefit of CDK 4/6 inhibitors as a replacement for traditional chemotherapy to improve outcomes in HER2+ breast cancer.

Prognostic role of the stromal tumor-infiltrating lymphocytes (TILs) in women with early ER+/HER2+ breast cancer (BC) in whom adjuvant chemotherapy (ChT) was omitted.

e12526 Background: Adjuvant systemic therapy in women with early ER+/HER2+ BC usually includes ChT, trastuzumab (T) and endocrine therapy (ET). High level of TILs is associated with better outcome in HER2+ disease. Here we explore the outcome and prognostic role of TILs in women with early ER+/HER2+ BC in whom ChT was omitted. Methods: Women with ER+ (IHC ≥ 1%) and HER2+ (IHC3+ and/or FISH ratio ≥ 2.0) early BC who underwent surgery between years 2006 and 2016 at the Institute of Oncology Ljubljana and did not receive adjuvant ChT were eligible for this study. Hematoxilin and eosin slides of primary tumors were retrieved and evaluated for the percentage of stromal TILs. Distant disease-free survival (DDFS) was estimated by the Kaplan-Meier method. The association between DDFS and TILs level was explored in the Cox proportional hazard model. Relative survival was used for estimating the probability of dying due to the breast cancer or other causes. Results: During the 10-year period 86 (29.4%) out of 292 women with early ER+/HER2+ BC who underwent surgery did not receive adjuvant ChT. ChT was omitted due to the stage I disease (n=30), comorbidities (n=25), older age (n=19), refusal of treatment (n=9) and other causes (n=3). Five (5.8%) and 81 (94.1%) women received T and ET, respectively. Their median age was 65.8 yrs (IQR 55.7, 75.6 yrs) and 45 (52.3%) had stage I disease. There were 53 (61.6%), 24 (27.9%) and 9 (10.4%) women with low (&lt;10%), intermediate (≤10% to &lt;40%) and high (≥ 40%) level of TILs, respectively. After median follow-up of 10 years 28 events (distant recurrence or death) occurred. The 10-year DDFS for those who did not receive ChT due to the stage I disease, comorbidities and older age was 91% (95% CI, 0.79 to 1.00), 38% (95% CI, 0.18 to 0.75]) and 26% (95% CI, 0.10 to 0.66) (p˂0.0001), respectively. After excluding women with stage I disease the estimated probability of dying due to the breast cancer and due to other causes was 26.7% and 26.5%, respectively. Overall, for every 10% increase in TILs the risk of distant recurrence or death was reduced for 18% (HR=0.82; 95% CI, 0.64 to 1.05) (p=0.11). In the multivariable Cox model, higher TILs level was a significant predictor of better DDFS (HR 0.75; 95% CI, 0.57 to 0.98) (p=0.041) (Table). Conclusions: Women with stage I ER+/HER2+ BC who do not receive adjuvant ChT and T but do receive adjuvant ET may still have a very good outcome. In contrast, survival of women who do not receive adjuvant ChT and T for other reasons is poor; however, only a half of those deaths are related to BC. TIL is a favourable prognostic biomarker which might be helpful when de-escalation of systemic therapy in women with ER+/HER2+ BC is considered.[Table: see text]

Cardiac Monitoring and Heart Failure in Advanced Breast Cancer Patients Treated With Trastuzumab in Ontario, Canada.

BackgroundTrastuzumab has improved patient outcomes in HER2 + breast cancer (BC) but carries a risk of cardiotoxicity. Routine cardiac imaging is recommended for advanced breast cancer (aBC) patients during trastuzumab treatment despite a lack of evidence that this improves patient outcomes. This study was conducted to understand predictive factors for cardiac events and determine the impact of cardiovascular monitoring in aBC.MethodsThis retrospective population-based cohort study included aBC patients treated with trastuzumab (all lines), in Ontario, Canada from 2007 to 2017. The overall cohort was divided into two groups; those who developed a cardiac event (CE) vs. those who did not. Patients with pre-existing heart disease were excluded. Logistic regression was performed to identify patient characteristics associated with an increased risk of CE.ResultsOf 2,284 patients with HER2 + aBC treated with trastuzumab, 167 (7.3%) developed a CE. Median age at first dose of trastuzumab was 57 (IQR 49–66); 61 (IQR 51–70) for patients with a CE. Median number of cycles was 16 (IQR 7–32); 21 (IQR 8–45) for patients with a CE (p < 0.01). Twelve (0.5%) patients died of cardiac causes; all had a prior CE. Increased risk of CEs was associated with age > 60 (OR 5.21, 95% CI 1.83–14.84, p = 0.05) and higher number cycles of trastuzumab (OR 1.01; 95% CI 1–101, p = 0.028).ConclusionThis is the first population-based study to report on CEs and cardiac monitoring in HER2 + aBC patients during trastuzumab-based therapy. Older age and longer treatment with trastuzumab were associated with an increased risk of a CE.

Trastuzumab/pertuzumab combination therapy stimulates antitumor responses through complement-dependent cytotoxicity and phagocytosis.

Two HER2-specific mAbs, trastuzumab and pertuzumab (T+P), combined with chemotherapy comprise standard-of-care treatment for advanced HER2+ breast cancers (BC). While this antibody combination is highly effective, its synergistic mechanism-of-action (MOA) remains incompletely understood. Past studies have suggested that the synergy underlying this combination occurs through the different mechanisms elicited by these antibodies, with pertuzumab suppressing HER2 heterodimerization and trastuzumab inducing antitumor immunity. However, in vivo evidence for this synergy is lacking. In this study, we found that the therapeutic efficacy elicited by their combination occurs through their joint ability to activate the classical complement pathway, resulting in both complement-dependent cytotoxicity and complement-dependent cellular phagocytosis of HER2+ tumors. We also demonstrate that tumor C1q expression is positively associated with survival outcome in HER2+ BC patients and that complement regulators CD55 and CD59 were inversely correlated with outcome, suggesting the clinical importance of complement activity. Accordingly, inhibition of C1q in mice abolished the synergistic therapeutic activity of T+P therapy, whereas knockdown of CD55 and CD59 expression enhanced T+P efficacy. In summary, our study identifies classical complement activation as a significant antitumor MOA for T+P therapy that may be functionally enhanced to potentially augment clinical therapeutic efficacy.

Abstract P1-18-09: Impact of prior adjuvant trastuzumab (aT) on clinical characteristics, patterns of recurrence and outcomes in 4145 patients with Her2 positive (HER2+) metastatic breast cancer (MBC)- Results from the French ESME UNICANCER program

Abstract Background: The management of HER2+ BC has changed dramatically with the introduction and widespread use of HER2-targeted therapies, especially in the adjuvant setting. It is well-known that de novo metastatic HER2+ breast cancer patients have better outcomes that women with metastatic relapse. This could be related both to a lead time bias, as well as to an ATRESS (adjuvant therapy-related shortening of survival) phenomenon [1]. Indeed, cancer treatments induce increased both clonal selection, as well as globally tumor resistance and agressivity [2]. However, there is relatively limited real-world information on the impact of adjuvant and neoadjuvant anti-HER2 targeted treatments on patterns of recurrence and outcomes of HER2+ MBC. Thus, the purpose of this study was to determine how and how long anti-HER2 targeted treatment in early setting impact outcomes of patients with HER2+ recurring BC. Methods: Since 2014, the 18 French Cancer Centers launched the Epidemiological Strategy and Medical Economics (ESME) program to provide real-world data on MBC patients (pts). All pts who started a 1st-line treatment for MBC between 01-Jan-2008 and 31-Dec-2017 were included. We examined clinical characteristics and outcomes (overall survival [OS] and time to 1st metastasis [TTM]) in patients with HER2+ MBC pretreated with trastuzumab in the (neo)adjuvant setting (aT) compared with trastuzumab-naïve patients and patients with de novo HER2+ MBC. Multivariate analyses adjusted for baseline demographic, prognostic factors, adjuvant treatment received and time to MBC. Results: Among the 23698 pts of the ESME database, 4145 were women treated in 1st line of a HER2+ MBC: 1716 pts (41%) had de novo and 2429 pts (59%) recurrent and 65% had Hormone Receptor (HR) + MBC; 53%, 26% and 21% had respectively 1, 2, or &amp;gt; 2 metastatic sites (64% visceral and 11% brain). With a median follow-up of 60.7 m, median OS is 42.4 m (95% CI: 40.1-45.0) for patients who relapsed. OS is significantly longer in de novo MBC: 64.7 m (95% CI: 60.2-73) (HRadjusted=0.68, 95% CI: 0.62-0.76, p &amp;lt; 0.0001). Among pts with recurrent MBC, 56% (1343) had received adjuvant trastuzumab (aT). As 1st-line therapy for MBC, 86 % of pts received HER2-targeted agents (74% T-based, 24% T-pertuzumab-based). Median TTM was 46.9 months (m): 57.6 m in HR+ and 30.2 m in HR-. Among pts with HR- diseases, 38% relapsed during the first 2 years of follow-up and 30% after 4 years (14.8%% and 56.9% in HR+ respectively). Among pts with recurrent MBC, crude median OS is inferior in pts who received aT, as compared to those who did not: 37.2 m (95% CI: 34.4-40.3) vs. 53.5 m (95% CI: 47.6-60.1), but this difference does not persist after adjustment for age, performans status, disease-free interval and number and type of metastatic sites in the multivariate model (HR=1.05, 95% CI: 0.91-1.22). A short disease-free interval (6-24 months compared to &amp;gt;48) remains, however, a strong adverse prognostic factor (HR=2.1, 95% CI: 1.82-2.50). Conclusions: The receipt of adjuvant trastuzumab does not predict for worse outcomes when adjusted to the other prognostic factors, among patients who relapsed during the 2008-2017 period. An ATRESS phenomenon is not suggested, although we cannot rule it out for those who relapsed within the initial 2 years. The much better prognosis of de novo MBC may be largely linked to lead time biases. Citation Format: Fanny Le Du, Matthieu Carton, Mahasti Saghatchian, David Perol, Barbara Pistilli, Etienne Brain, Delphine Loirat, Laurence Vanlemmens, Thomas Vermeulin, Christelle Levy, Anthony Goncalves, Mony Ung, Marie Robert, Anne Jaffre, Mathieu Robain, Suzette Delaloge, Véronique Dieras. Impact of prior adjuvant trastuzumab (aT) on clinical characteristics, patterns of recurrence and outcomes in 4145 patients with Her2 positive (HER2+) metastatic breast cancer (MBC)- Results from the French ESME UNICANCER program [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 P1-18-09.