HER2 Breast Cancer Patients Research Articles

Can negative axillary ultrasound reliably predict pathologically negative axillary lymph node status in breast cancer patients with cT ≤3 cm, cN0, and HER2-positive?-a retrospective, single-institution study.

Breast cancer (BC) is the leading cancer in women globally, with human epidermal growth factor receptor 2 (HER2)-positive subtype accounting for 15-20% of cases and exhibiting aggressive behavior. The standard of care for operable BC has evolved to include neoadjuvant systemic therapy, which can guide treatment decisions and improve outcomes, particularly in HER2+ BC. This study aims to investigate whether axillary ultrasound has a good negative predictive value (NPV) for early HER2 BC patients and to identify clinicopathological factors that can impact the axillary lymph node metastasis. This retrospective, single-center study evaluated the medical records of 135 patients with HER2+ BC, cT ≤3 cm, and clinically negative axillary lymph nodes from 2018 to 2020. The study aimed to determine the NPV of axillary ultrasound for pathologically negative axillary lymph node status and to identify factors associated with axillary lymph node metastasis. The NPV of axillary ultrasound was 78.5%, increasing to 89.6% and 93.3% when considering 0-1 and 0-2 metastatic lymph nodes, respectively. Lymphovascular invasion (LVI) was significantly associated with axillary lymph node metastasis, with a 2.2-fold increased risk. Axillary ultrasound shows good predictive value for axillary lymph node negativity in HER2+ BC patients with small tumors. However, the presence of LVI increases the risk of metastasis, suggesting a need for neoadjuvant chemotherapy. These findings contribute to personalized treatment strategies for early HER2+ BC, emphasizing the role of axillary ultrasound in clinical decision-making.

Major pathologic response and long-term clinical benefit in hormone receptor-positive, human epidermal growth factor receptor 2-negative breast cancer after neoadjuvant chemotherapy

BackgroundThe majority of HR+/HER2-breast cancer patients can also achieve long-term survival despite not attaining pCR, indicating limited prognostic value of pCR in this population. This study aimed to identify novel pathologic end points for predicting long-term outcomes in HR+/HER2-breast cancer after neoadjuvant chemotherapy. MethodsWe analyzed HR+/HER2-breast cancer patients with stage II-III tumors who underwent curative surgery after neoadjuvant chemotherapy from three hospitals. Major pathologic response (MPR), defined as the presence of Miller-Payne grades 3–5 and positive lymph node ratio of ≤10 %, was used as a pathological evaluation indicator. We assessed the association between MPR and event-free survival (EFS) and performed Multivariable Cox regression to identify independent factors associated with EFS. ResultsFrom January 2010 to December 2020, 386 patients were included in the final analysis. 28 patients (7.3 %) achieved pCR and 118 patients (30.6 %) achieved MPR. The median duration of follow-up was 54.4 months,5-year EFS was 87 % in the MPR group vs. 68 % in the non-MPR group. Multivariate analysis showed that low PR expression, high clinical stage, lower Miller–Payne grades and Positive lymph node ratio were independent poor prognostic factors for EFS (all P values < 0.05). The prognostic effect of MPR remained in multivariable models (hazard ratio (HR), 0.45; 95 % confidence interval (CI), 0.26–0.76; P = 0.008), In non-pCR patients, those who achieved MPR exhibited a similar EFS compared with pCR patients (HR, 2.25; 95 % CI, 0.51–9.84; P = 0.28). ConclusionMPR may be a novel pathologic end point in HR+/HER2-breast cancer after neoadjuvant chemotherapy, holding greater applicability in the prognosis evaluation than pCR.

Disease landscape of advanced HER2-breast cancer patients by treatment line in three EU countries and USA.

Aim: To report treatment patterns and quality of life (QoL) in HER2-negative advanced breast cancer patients.Methods: Data were drawn from a cross-sectional survey in Europe and USA.Results: Hormone plus targeted therapy was the most frequent first-line (1L, 62%) and second-line (2L, 45%) treatment for HR+/HER2-patients. Chemotherapy was most frequent at third-line or greater (3L+, 39%) for HR+/HER2- patients, 2L (51%) and 3L+ (48%) for triple negative breast cancer (TNBC) patients. Time to progression was 13.8 (2L) and 11.0 (3L+) months for HR+/HER2- patients. No comparisons were observed for TNBC patients. EQ-5D-5L scores were highest in patients at 1L and lowest at 3L+.Conclusion: Reduced QoL and treatment response were reported in patients at later lines of therapy.

Abstract 7613: Association of KAT6A expression with clinical outcomes in previously treated HR-positive and HER2-negative metastatic breast cancer

Abstract Background: KAT6A is a histone acetyltransferase that regulates gene transcription, cell cycle, senescence and cell differentiation. It is amplified and overexpressed in a subset of breast cancers and may positively regulate ER expression. Gene expression analysis in tumor samples from the PALOMA-3 study was conducted to explore potential associations of KAT6A and related biomarkers with enhanced benefit from the addition of palbociclib (PAL) to fulvestrant (FUL) in HR-positive, HER2-negative breast cancer. Methods: The PALOMA-3 trial randomly assigned 521 endocrine pretreated patients with metastatic breast cancer, including those with prior exposure to chemotherapy, to receive PAL+FUL or placebo (PBO) +FUL. Exploratory analysis was conducted on tumor gene expression levels of KAT6A and KAT6B to evaluate their association with the effect of PAL+FUL vs PBO+FUL on progression-free survival (PFS) using Cox proportional hazards regression analysis, with gene expression as a continuous variable or dichotomized by median. Treatment by biomarker interaction effect was also tested. Results: In the PALOMA-3 trial, the analyses were conducted in 214 patients (PAL+FUL, 137 patients; PBO+FUL, 77 patients) with baseline tissue profiled, which included 165 patients with prior chemotherapy (PAL+FUL, 101 patients; PBO+FUL, 64 patients). In patients with KAT6A data, a trend of better treatment effect (interaction p = 0.54) was observed in those with low KAT6A mRNA expression (median PFS on PAL+FUL was 11.04 months (m) and PBO+FUL was 3.65 m, HR = 0.52, 95% CI 0.32-0.85, log rank p = 0.008) versus high KAT6A expression (median PFS on PAL+FUL was 13.90 m and PBO+FUL was 11.20 m, HR = 0.66, 95% CI 0.39-1.13, p = 0.126). A treatment effect was observed in patients with prior exposure to chemotherapy who had low KAT6A expression (median PFS on PAL+FUL was 9.53 m and PBO+FUL was 3.66 m, HR = 0.55, 95% CI 0.33-0.94, p = 0.027), while this was not observed in those with high KAT6A expression (median PFS on PAL+FUL was 11.43 m and PBO+FUL was 11.33 m, HR = 1.13, 95% CI 0.61-2.09, p = 0.71), with the interaction p value of 0.12. No treatment difference was detected between treatment arms and expression levels of KAT6B (interaction p values of 0.48 and 0.36 in all patients and in those with prior chemo respectively). Potential interaction of KAT6A with other genes including ESR1 will be discussed. Conclusions: Low tumor KAT6A mRNA expression identified patients with relatively greater benefit from addition of PAL to FUL especially in those with prior exposure to both chemo- and endocrine therapies. The data support further investigation of KAT6A and its related biomarkers and their association with CDK4/6 inhibitors and/or endocrine therapy in HR+/HER2-breast cancer patients and to test if a KAT6 inhibitor can enhance CDK4/6 inhibitor and/or endocrine therapy efficacy in tumors with high KAT6A expression. Citation Format: Massimo Cristofanilli, Li Liu, Shibing Deng, Xin Huang, Fabrice André, Sibylle Loibl, Angela DeMichele, Eric Gauthier, Yuan Liu, Nicholas C. Turner. Association of KAT6A expression with clinical outcomes in previously treated HR-positive and HER2-negative metastatic breast cancer [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 7613.

The significance of the correlation between the cell proliferative index Ki-67 and the human epidermal growth factor HER2 in breast cancer patients who received neoadjuvant therapy

The significance of the correlation between the cell proliferative index Ki-67 and the human epidermal growth factor HER2 in breast cancer patients who received neoadjuvant therapy

Correlation between Risk Factors and Protein Expression of ER, PR, and HER-2 in Breast Cancer Patients: A Population-Based Study in Makassar Indonesia

Background: Breast cancer is a condition characterized by abnormal and uncontrollable growth of cells in breast tissue. According to Global Cancer Statistics 2020, it ranks as the leading cause of female cancer mortality. The disease has four subtypes defined by protein expression, namely Luminal A (ER/PR (+), HER2 (-)), Luminal B (ER/PR (+), HER2 (+)), triple-negative/basal-like (ER, PR, HER2 (-)), and HER2-enriched (ER (-), PR (-), HER2 (+)), each with distinct characteristics influenced by various risk factors. Therefore, this study aimed to explore the correlation between breast cancer risk factors and protein expression of ER, PR, and HER2. Methods: The cross-sectional analytical study was conducted in Makassar, Indonesia, using secondary data from 259 breast cancer patients. Information on ER, PR, HER2 expression, and patient risk factors such as age, history of hormonal contraceptive use, and family history of breast cancer were extracted from medical records and subjected to statistical analysis using the Chi-square test, with significance set at p &lt; 0.05. Results: The results showed that there was a significant correlation between age ≥ 40 years and the expression of ER, PR, and HER2 (p &lt; 0.005). However, no significant correlations were observed between family history and hormonal contraceptive use with ER, PR, and HER2 expression. Conclusions: This study established a meaningful correlation between risk factors of age and breast cancer subtypes based on ER, PR, and HER2 expression.

Employing Pd nanoparticles decorated on halloysite nanotube/carbon composite for electrochemical aptasensing of HER2 in breast cancer patients

An effective biosensing platform is described based on halloysite nanotube/carbon composite decorated with Pd nanoparticles (HNT/C@Pd NPs). A novel electrochemical aptasensor was designed using the proposed nano-platform to determine human epidermal growth factor receptor 2 (HER2), a breast cancer biomarker. Inherently, aptasensing interfaces provide high sensitivity and selectivity for tumor markers owing to the high specific surface area of HNT/C and good conductivity stems from deposition of Pd NPs into HNT/C composite. With a correlation coefficient of 0.996, the electrochemical aptasensor demonstrated a wide linear range from 0.03 ng/mL to 9 ng/mL. The limit of detection (LOD) of the established assay was 8 pg/mL based on S/N = 3 method. Further, the designed biosensor demonstrated acceptable selectivity, good reproducibility, and high stability. The applicability of the impedimetric sensor in human serum samples was also examined and compared to enzyme-linked immunosorbent assay (ELISA) assay (p-value >0.05). Based on the results, it was found that the proposed methodology can be used in quantification of breast cancer markers for early diagnosis and treatment.

Development of cardiac risk prediction model in patients with HER-2 positive breast cancer on trastuzumab therapy

Background25% of all breast cancer patients have HER-2 overexpression. Breast Cancer patients with HER-2 overexpression are typically treated with HER-2 inhibitors such as Trastuzumab. Trastuzumab is known to cause a decrease in left ventricular ejection fraction. The aim of this study is to create a cardiac risk prediction tool among women with Her-2 positive breast cancer to predict cardiotoxicity.MethodUsing a split sample design, we created a risk prediction tool using patient level data from electronic medical records. The study included women 18 years of age and older diagnosed with HER-2 positive breast cancer who received Trastuzumab. Outcome measure was defined as a drop in LVEF by more than 10% to less than 53% at any time in the 1-year study period. Logistic regression was used to test predictors.ResultsThe cumulative incidence of cardiac dysfunction in our study was 9.4%. The sensitivity and specificity of the model are 46% and 84%, respectively. Given a cumulative incidence of cardiotoxicity of 9%, the negative predictive value of the test was 94%. This suggests that in a low-risk population, the interval of screening for cardiotoxicity may be performed less frequently.ConclusionCardiac risk prediction tool can be used to identify Her-2 positive breast cancer patients at risk of developing cardiac dysfunction. Also, test characteristics in addition to disease prevalence may inform a rational strategy in performing cardiac ultrasound in Her-2 breast cancer patients. We have developed a cardiac risk prediction model with high NPV in a low-risk population which has an appealing cost-effectiveness profile.

Adjuvant Therapy in Breast Cancer Patients With Microscopic Residual Disease

IntroductionSurgical resection is the gold standard for early-stage breast cancer. Positive surgical margins are associated with poor outcome. Endocrine therapy (ET) is recommended as primary systemic treatment for hormone receptor positive (HR+) breast cancer after surgery. We hypothesized that chemoenocrine therapy (CET) would not be associated with improved survival relative to ET for patients with positive margins. Materials and methodsThe National Cancer Database was queried for pathologic stage I HR + HER2-breast cancer patients treated with partial mastectomy and adjuvant whole-breast irradiation between 2004 and 2017. The adjuvant treatment approaches to positive surgical margins were investigated and compared. Overall survival was compared between systemic treatment groups using multivariable cox proportional hazards regression. ResultsAmong 228,453 patients, a positive surgical margin (microscopic residual disease, R1) was identified in 3561 (1.6%) patients. Compared with complete resections, positive margin was associated with inferior overall survival (hazard ratio [HR] = 1.276, P = 0.003). Among the R1 patients, 78.7% received ET only, 11.7% received CET, 1.2% received chemotherapy only, and 8.5% received no systemic therapy. After controlling for patient, facility, and tumor characteristics, ET provided greatest survival benefit (relative to no therapy, HR = 0.378, P < 0.001) followed by CET (HR = 0.446, P = 0.020). Compared with ET alone, CET is not associated with additional overall survival benefit (HR = 1.179, P = 0.595). ConclusionsCET appeared not to be associated with an improved overall survival in early stage HR + HER2-breast cancer with microscopic residual disease relative to ET. Positive surgical margins therefore are probably not a relevant clinical factor for adjuvant chemotherapy decision-making.

Clinical Features and Prognosis Analysis of Hormone Receptor-Positive, HER2-Negative Breast Cancer with Differential Expression Levels of Estrogen and Progesterone Receptors: A 10-Year Retrospective Study.

Estrogen and progesterone receptor status can predict breast cancer patient prognosis and treatment sensitivity, but research on low ER and PR levels and expression balance remains limited. From January 2010 to October 2016, 283 ER+/PR+/HER2-breast cancer patients who met the inclusion criteria were enrolled and divided into the H group (ER > 10%, N = 261) and the L group (1% ≤ ER ≤ 10%, N = 22). Groups were further divided into the HH group (ER > 10%/PR > 20%, N = 201), the HL group (ER > 10%/ER 1% ≤ PR ≤ 20% PR, N = 60), the LH group (1% ≤ ER ≤ 10%/PR > 20%, N = 5), and the LL group (1% ≤ ER ≤ 10%/1% ≤ PR ≤ 20%, N = 17). The LH group was excluded due to its small size, leaving the clinical and prognostic characteristics of 2 large groups and 3 subgroups to be analyzed. L group patients had significantly more stage N2 axillary lymph nodes than H group patients (31.8% vs. 9.2%, P = 0.007). Age (P = 0.011), menopause status (P = 0.001), and tumor size (P = 0.024) were significantly different in the HL vs. HH and LL groups. Five-year DFS (94.6% vs. 77.0%, P < 0.001) and 5-year OS (97.2% vs. 85.8%, P = 0.001) rates significantly differed between HH and HL. No significant differences in 5-year DFS (77.0% vs. 81.9%, P = 0.564) or 5-year OS (85.8% vs. 87.8%, P = 0.729) rates were observed between HL and LL; the OS rates of HL and LL were similar. In the group of ER+/PR+/HER2-patients, there was no significant prognostic difference between ER-low positive and ER-high positive groups, but low PR expression was significantly associated with a worse prognosis. The role of ER and PR balance in breast cancer progression and individualized treatment requires further investigation.

Redox Status Response of Physical Exercise Training in Women with Breast Cancer during Trastuzumab Therapy.

Trastuzumab is indicated in the adjuvant setting for the early and intermediate stages of breast cancer (BC) positive for epidermal growth factor receptor 2 (HER2). Although HER2 in BC patients tends to disrupt pro-oxidant and inflammatory signaling, the influence of trastuzumab in modulating this process remains unknown. Due to the absence of any chemotherapeutic or chemoprophylactic agents for trastuzumab-induced side effects, this study investigated the potential role of regular physical exercise in modulating the antioxidant defenses, oxidative stress, and nitrosative damage in BC patients during trastuzumab treatment. Aim: The study aimed to analyze the relationship between regular physical activity and the redox status in women with BC during trastuzumab therapy. Materials and methods: We observed 50 BC patients during trastuzumab therapy in two groups: one that undertook moderately intensive supervised physical exercises, and a second that performed physical activity according to the recommendations for cancer patients, along with a third (control) group of healthy women. Results: The antioxidant enzyme and non-enzymatic antioxidant activities were significantly higher in the exercised group compared with the other participants. The concentrations of lipid and protein oxidative damage and nitrosative stress products were significantly higher in both BC groups than in the healthy controls. Conclusions: Trastuzumab treatment stimulates a redox response in BC patients. The results highlight the oxidative imbalance in parallel with regular physical training in women with BC during trastuzumab therapy. Further studies are needed to analyze different intensities and levels of physical training in women with BC during trastuzumab treatment.

IKZF3 amplification frequently occurs in HER2-positive breast cancer and is a potential therapeutic target.

Breast cancer is one of the leading causes of cancer death in women, and although treatment outcome has substantially improved in the past decades, advanced or metastatic breast cancers still carry a poor prognosis. Gene amplification is one of the frequent genetic alterations in cancer, and oncogene amplification may be associated with cancer aggressiveness and oncogenicity. Targeting amplified genes such as HER2 has vastly improved disease outcome and survival, and anti-HER2 therapeutics have revolutionized the standard of care in HER2 breast cancer. Besides currently known druggable gene amplifications including ERBB2 and FGFR2, other frequently amplified genes are relatively less well known for function and clinical significance. By querying four large databases from TCGA and AACR-Genie, from a total of 11,890 patients with invasive ductal breast carcinoma, we discover IKZF3, CCND1, ERBB2 to be consistently amplified across different cohorts. We further identify IKZF3 as a frequently amplified gene in breast cancer with a prevalence of 12-15% amplification rate. Interestingly, IKZF3 amplification is frequently co-amplified with ERBB2/HER2, and is also associated with worse prognosis compared to IKZF3 non-amplified cancers. Analysis of HER2 breast cancer patients treated with trastuzumab revealed decrease in both ERBB2/HER2 and IKZF3 expression. Further investigation using the DepMap for gene dependency by genome-wide CRISPR screening revealed dependence on IKZF3 in HER2 breast cancer cell lines. Our study utilized an integrative analysis of large-scale patient genomics, transcriptomics and clinical data to reveal IKZF3 as a frequently amplified gene, and suggest a potential role of IKZF3 as a druggable target for HER2 breast cancer.

Novel Therapies and Strategies to Overcome Resistance to Anti-HER2-Targeted Drugs.

Simple SummaryDrug resistance is the “Achilles’ heel” in current oncology. In this sense, the clinical management of HER2 breast carcinomas (tumors with overexpression/amplification of the ErbB2/HER2 oncogene) is still a challenge. Although a variety of anti-HER2 therapies (anti-HER2 antibodies, antibody–drug conjugates, and tyrosine kinase inhibitors) are available for these patients, the frequent appearance of innate and acquired tumor resistance to these treatments creates an urgent need to develop new and more effective therapeutic approaches. In this review, we discuss the most relevant clinical and pre-clinical advances in therapeutic strategies aimed at overcoming drug resistance in HER2 breast cancer patients in different stages of the disease.The prognosis and quality of life of HER2 breast cancer patients have significantly improved due to the crucial clinical benefit of various anti-HER2 targeted therapies. However, HER2 tumors can possess or develop several resistance mechanisms to these treatments, thus leaving patients with a limited set of additional therapeutic options. Fortunately, to overcome this problem, in recent years, multiple different and complementary approaches have been developed (such as antibody–drug conjugates (ADCs)) that are in clinical or preclinical stages. In this review, we focus on emerging strategies other than on ADCs that are either aimed at directly target the HER2 receptor (i.e., novel tyrosine kinase inhibitors) or subsequent intracellular signaling (e.g., PI3K/AKT/mTOR, CDK4/6 inhibitors, etc.), as well as on innovative approaches designed to attack other potential tumor weaknesses (such as immunotherapy, autophagy blockade, or targeting of other genes within the HER2 amplicon). Moreover, relevant technical advances such as anti-HER2 nanotherapies and immunotoxins are also discussed. In brief, this review summarizes the impact of novel therapeutic approaches on current and future clinical management of aggressive HER2 breast tumors.

Treatment of HR+/HER2− breast cancer in urban mainland China: results from the CancerMPact Survey 2019

PurposeTo report the treatment utilization patterns for hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2−) breast cancer in urban mainland China (CancerMPact®).MethodsThe results presented are from an online survey conducted in September 2019 with 45 physicians treating breast cancer patients from 11 cities in mainland China.ResultsSurveyed physicians reported that Stage I HR+/HER2(−) breast cancer patients are often treated with surgery alone (42%), whereas the use of surgery in combination with systemic therapy with or without radiotherapy increases in later stages (Stage II 67%, Stage III 77%). Doxorubicin–cyclophosphamide (AC)-based regimens were the most common in both the neoadjuvant and adjuvant settings in HR+/HER2(−) breast cancer patients, across all stages. In metastatic patients, use of surgery and radiotherapy decreases in favor of utilization of systemic therapy alone. Pre- and post-menopausal metastatic patients were frequently treated with hormone therapy or AC-based regimens in first line. Regardless of the first-line therapy administered, capecitabine-based regimens were commonly used in second line. In third line, chemotherapy regimens containing capecitabine or gemcitabine were given to nearly 40% of HR+/HER2(−) breast cancer patients. There were no standard of care regimens established for fourth or greater lines of treatment. In metastatic HR+/HER2(−) breast cancer, physicians reported 50% objective response rates in first-line settings with a progression-free survival of 16 months.ConclusionHR+/HER2(−) breast cancer patients in urban mainland China were prescribed chemotherapy regimens more frequently than CDK4/6 inhibitors. Treatment practices varied, with physicians reporting the use of multiple modalities and treatment regimens for their patients.

Tumor-infiltrating lymphocytes (TILs)/volume and prognosis: The value of TILs for survival in HER2 and TN breast cancer patients treated with chemotherapy

Background and objectiveThe use of the tumor microenvironment as a target in creating treatment modalities and as a biomarker in predicting treatment response has become increasingly important. Tumor-infiltrating lymphocytes (TILs), located in the tumor microenvironment, are the fundamental elements of the specific immunological response against tumor cells and have prognostic importance in many types of cancer. Materials and methodsBetween January 2010 and June 2021, 350 patients who were operated on in our hospital and met the study criteria were included in the study. TILs and tumor-infiltrating lymphocyte volume (TILV) were evaluated in hematoxylin-eosin sections of the patients. ResultsPresence of high stromal TILs was associated with improved survival (p = 0.036), distant metastasis (p = 0.009), high nuclear and histological grade (p < 0.001), estrogen receptor (ER) and progesterone receptor (PR) negativity (p < 0.001), high Ki-67 proliferation index (<0.001), HER2 expression (p = 0.026) level, perineural invasion (p = 0.048), adjuvant chemotherapy (p = 0.005) and radiotherapy (p = 0.055) treatment.High TILV was associated with high nuclear and histological grade (p < 0.001), ER and PR negativity (p < 0.001), HER2 positivity (p = 0.013), high Ki-67 proliferation index (p = 0.001) and high tumor size (p = 0.0011). There was no significant relationship between survival (p = 0.343), distant metastasis (p = 0.632), lymph node metastasis (p = 0.141) and sTIL volume. ConclusionTILs are an indicator of an anti-tumor immune response, and tumor suppressor efficiency is increased by chemotherapy and immunotherapy treatments. It is one of the factors that determine the success of the treatment. The tumor-infiltrating lymphocyte is an important parameter that can help determine the patient groups to be treated with chemotherapy, prevent unnecessary complications, and be quickly evaluated in all laboratories without any expense.

Abstract P2-12-06: Pathological response-guided postoperative treatment strategy for positive HR/negative HER2 and positive lymphnodes breast cancer patients with non-responsive pathological results to neoadjuvant chemotherapy

Abstract Objective: No consensus up to date suggesting whether patients with positive HR/negative HER-2 and positive lymph nodes breast cancer should receive additional adjuvant chemotherapy following a poor response to neoadjuvant chemotherapy to acquire a better DDFS. The main aim of this trial is to compare the 5-year DDFS between additional adjuvant chemotherapy plus endocrine therapy group and endocrine alone group following 4 cycles neoadjuvant chemotherapy. Method: A multicenter, open-label, randomized, controlled, phase 3 trial was conducted. All patients enrolled in the study were HR+ HER2- LN+ breast cancer patients completing four cycles neoadjuvant chemotherapy, with a non-responsive pathological result to neoadjuvant chemotherapy. The non-responsive criterion was defined as Miller and Payne staging grade1 to grade 3, or any grade of Miller and Payne staging but residual positive lymph nodes were found in surgical specimen. All enrolled patients were randomly assigned to receive four cycles non-cross resistant regimen plus endocrine therapy, or endocrine therapy alone. The primary endpoint was DDFS, and the secondary endpoint was iDFS and OS. Result: From October 2010 to September 2018, a total of 391 patients were enrolled for eligibility. The final ITT analysis compromised 379 patients (187 in adjuvant chemotherapy plus endocrine therapy group, and 192 in endocrine therapy alone group). After a median follow-up of 72.4 months, the 5-year distant disease free survival estimate was 92% (95% CI 88-96) in the adjuvant chemotherapy group and 90% (86-94) in the endocrine therapy alone group (HR 0.79, 95% CI 0.45-1.37) (P=0.401). In the prespecified CEF subgroup, the 5-year DDFS was 94% (95% CI 90-98) in adjuvant chemotherapy group, and 91% (95% CI 87-94) in endocrine group (HR 0.68, 95% CI 0.36-1.30) (P=0.249). In the exploratory analysis, we found a better 5-year DDFS trend in adjuvant chemotherapy group in ypN+ patients in CEF subgroup (P=0.196). Conclusion: A better 5-year DDFS trend in additional adjuvant chemotherapy plus endocrine therapy can be found for patients with positive HR/negative HER-2 and positive lymph nodes following a poor response to neoadjuvant chemotherapy. Citation Format: Yang Yang, Xue Chen, Zhaoqing Fan, Yingjian He, Yuntao Xie, Jinfeng Li, Tianfeng Wang, Tao Ouyang. Pathological response-guided postoperative treatment strategy for positive HR/negative HER2 and positive lymphnodes breast cancer patients with non-responsive pathological results to neoadjuvant chemotherapy [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 P2-12-06.

Contralateral parenchymal enhancement on MRI is associated with tumor proteasome pathway gene expression and overall survival of early ER+/HER2-breast cancer patients

PurposeTo assess whether contralateral parenchymal enhancement (CPE) on MRI is associated with gene expression pathways in ER+/HER2-breast cancer, and if so, whether such pathways are related to survival. MethodsPreoperative breast MRIs were analyzed of early ER+/HER2-breast cancer patients eligible for breast-conserving surgery included in a prospective observational cohort study (MARGINS). The contralateral parenchyma was segmented and CPE was calculated as the average of the top-10% delayed enhancement. Total tumor RNA sequencing was performed and gene set enrichment analysis was used to reveal gene expression pathways associated with CPE (N = 226) and related to overall survival (OS) and invasive disease-free survival (IDFS) in multivariable survival analysis. The latter was also done for the METABRIC cohort (N = 1355). ResultsCPE was most strongly correlated with proteasome pathways (normalized enrichment statistic = 2.04, false discovery rate = .11). Patients with high CPE showed lower tumor proteasome gene expression. Proteasome gene expression had a hazard ratio (HR) of 1.40 (95% CI = 0.89, 2.16; P = .143) for OS in the MARGINS cohort and 1.53 (95% CI = 1.08, 2.14; P = .017) for IDFS, in METABRIC proteasome gene expression had an HR of 1.09 (95% CI = 1.01, 1.18; P = .020) for OS and 1.10 (95% CI = 1.02, 1.18; P = .012) for IDFS. ConclusionCPE was negatively correlated with tumor proteasome gene expression in early ER+/HER2-breast cancer patients. Low tumor proteasome gene expression was associated with improved survival in the METABRIC data.

Abstract 1414: Effect of E7090, an FGFR1-3 selective inhibitor, on resistance to a CDK4/6 inhibitor and endocrine therapy in ER(+)/HER2(-) breast cancer preclinical models

Abstract Introduction: The fibroblast growth factor receptor (FGFR) signaling has a crucial role in proliferation, survival, migration, and drug resistance of cancer cells, as well as tumor angiogenesis. Moreover, gene alterations of FGF/FGFR were reported after treatment of a CDK4/6 inhibitor and endocrine therapy (ET) in ER(+)/HER2(-) breast cancer (BC) patients, suggesting FGF/FGFR signaling mediates resistance to these therapies. E7090, an orally available FGFR1-3 selective inhibitor, is currently under evaluation in a Phase 2 study in patients with unresectable advanced or metastatic cholangiocarcinoma with FGFR2 gene fusion (NCT04238715), and a Phase 1 study as a monotherapy or in combination with fulvestrant (FUL) or exemestane for ER(+)/HER2(-) BC patients (NCT04572295). In this study, we present the roles of FGF/FGFR signaling in resistance to a CDK4/6 inhibitor and/or ET, and activities of E7090 on drug resistance in preclinical ER(+)/HER2(-) BC cell lines and PDx models. Results: Antitumor activities of E7090 (25 or 50mg/kg, Q1Dx14 or x21, p.o.) were evaluated using five ER(+)/HER2(-) BC PDx models, OD-BRE-0438, -0450, -0188, -0704, and IM-BRE-556 with or without prior treatment of FUL (5 mg/mouse, Q7Dx2, s.c.)+palbociclib (PAL, 100mg/kg, Q1Dx14, p.o.). Among them, OD-BRE-0438 and -0704 showed higher sensitivities to E7090 with prior FUL+PAL than without it, and E7090 showed tumor regression in the OD-BRE-0438 model only with prior FUL+PAL. In these two models, FUL+PAL treatment upregulated expressions of several FGF ligands mRNA (qPCR) and FGFRs protein (IHC) in tumors. To evaluate the activities of FGF/FGFR signaling on sensitivities to FUL or FUL+PAL, in vitro cell proliferation assay using ER(+)/HER2(-) BC cell lines, MCF-7, ZR-75-1, and HCC1428 were performed in the presence of FGF2 and FGF10, and decreased sensitivities to FUL or FUL+PAL were observed. Furthermore, co-treatment with E7090 restored the sensitivity to those drugs in cultured cell lines. In consistent with in vitro results, FUL in combination with E7090 showed a combination antitumor activity in the OD-BRE-0438 model, in which expressions of several FGF ligands mRNA and FGFR2 protein in tumors showed a tendency of upregulation by FUL. Conclusion: In ER(+)/HER2(-) BC PDx models, FGFs/FGFRs expression in tumors were induced by treatment of FUL and/or PAL, and antitumor activity of E7090 was enhanced with prior FUL+PAL. In vitro study using cultured ER(+)/HER2(-) BC cell lines indicated that sensitivity against FUL or FUL+PAL was decreased by FGFR activation. Furthermore, a combination antitumor activity of E7090 and FUL was observed in the OD-BRE-0438 model. These data suggest that activation of FGF/FGFR signaling confer the resistance to a CDK4/6 inhibitor and/or ET, and E7090 shows antitumor activity against ER(+)/HER2(-) BC with prior a CDK4/6 inhibitor and/or ET. Citation Format: Satoshi Kawano, Sayo Fukushima, Kyoko Nishibata, Ryu Gejima, Yuki Niwa, Yasuhiro Funahashi, Saori Watanabe Miyano. Effect of E7090, an FGFR1-3 selective inhibitor, on resistance to a CDK4/6 inhibitor and endocrine therapy in ER(+)/HER2(-) breast cancer preclinical models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1414.

P16-3 Maintenance therapy in HER2 and hormone receptor-positive breast cancer

After the standard first-line treatment for HER2 and hormone receptor-positive breast cancer, maintenance therapies are still controversial. Here, we report the real-world data of trastuzumab plus endocrine therapy compared with trastuzumab plus chemotherapy in HER2 and hormone receptor-positive metastatic breast cancer. This retrospective, multicenter, observational cohort study enrolled women aged 18 years or older with measurable or evaluable HER2 and hormone receptor-positive metastatic breast cancer who received chemotherapy and trastuzumab as first-line treatment between January 2009 and October 2019. We evaluated the efficacy and safety of trastuzumab plus endocrine therapy and trastuzumab plus chemotherapy. 102 patients were selected: 67 (65.7%) patients received trastuzumab plus endocrine therapy including aromatase inhibitors, fulvestrant, tamoxifen, or toremifene. While 35 (34.3%) patients received trastuzumab plus chemotherapy including capecitabine or vinorelbine as maintenance therapy. Maintenance endocrine therapy significantly improved progression-free survival (PFS) compared with chemotherapy (median progression-free survival 10.6 months [95% CI 8.609-12.658] vs 6.7 months [5.276-8.058], respectively; adjusted hazard ratio [HR] 0.648 [95% CI 0.428-0.981], p=0.040). The median PFS in patients without brain metastasis was 10.8 months (95% CI 9.380-12.154) in the endocrine therapy group versus 6.7 months (5.202-8.132) in the chemotherapy group (HR 0.485 [95% CI 0.303-0.777]), p=0.003). The most common adverse event was arthralgia (8,12%) in the endocrine therapy group, while hand-foot syndrome (25,71%) occurred in the chemotherapy group. Maintenance endocrine therapy could improve the survival of HER2 and hormone receptor-positive metastatic breast cancer patients.

Systemic treatment of HER2-positive breast cancer patients with brain metastases: current status and exploratory case study in a Portuguese cohort

Over the last years, the incidence of brain metastases in HER2 breast cancer patients has increased. Surgery and radiotherapy are the current standard local therapies. Nevertheless, it is unclear which and when systemic treatment should be applied in addition to local treatment. This work aims to present an updated review of current systemic treatment options for patients with HER2+ metastatic breast cancer with brain metastases and to present a case study of clinical cases that occurred in a Portuguese population. The methodology of this work included a literature search in PubMed for the impact of HER2-targeting agents, such as pertuzumab, trastuzumab emtansine (T-DM1), lapatinib, neratinib, trastuzumab deruxtecan, and tucatinib in the treatment of patients with HER2+ breast cancer with brain metastases. Then, a cohort of Portuguese patients with HER2+ breast cancer (n=44) was analyzed. In this exploratory study, considering a follow-up of 23.9 months, three patients (6.8%) developed brain metastases despite having shown a complete pathological response. The role of systemic treatment for patients with HER2 breast cancer with brain metastases has rapidly evolved following recent successes in phase II and III clinical trials. The biggest challenge is how to integrate systemic and local treatment in the management of these patients.