Positive Breast Cancer Patients Research Articles

Pharmacologic Induction of ERα SUMOylation Disrupts Its Chromatin Binding.

Estrogen receptor α (ERα)-positive breast cancer patients are typically treated with ERα inhibitors, including selective estrogen receptor modulators (SERMs) and selective estrogen receptor degraders (SERDs). However, the distinct pharmacological properties of various ERα inhibitors remain incompletely understood. In this study, we employed formaldehyde cross-linking followed by ERα immunoprecipitation and mass spectrometry to reveal that fulvestrant, the first FDA-approved SERD, induces the interaction between ERα and SUMO E3 ligases PIAS1 and PIAS2. Biochemical and genomic assays confirmed that fulvestrant induces SUMOylation of ERα, which inhibits ERα's binding to chromatin DNA. In addition, raloxifene (a SERM) and elacestrant (the first FDA-approved oral SERD) were identified as compounds that similarly induce ERα SUMOylation and inhibit its chromatin interaction. Our findings reveal a mechanism by which select ERα inhibitors disrupt ERα function through SUMOylation, offering insights for the development of next-generation ERα-targeted therapies.

7615 Genomic Consequences of GRHL2 Overexpression in ER+ Breast Cancer Cells

Abstract Disclosure: K.O. Allen: None. C. Zheng: None. N. Solodin: None. M.S. Ozers: Owner/Co-Owner; Self; Proteovista, LLC. C.L. Warren: None. P.E. Messa: None. D.T. Vogt: None. E.T. Alarid: None. Breast cancer progression is characterized by the presence and prevalence of metastatic disease. At a genomic level, metastasis can be facilitated via rearrangement of the chromatin landscape to expose oncogenic genes for transcription. Grainyhead like protein 2 (GRHL2) is a nuclear transcription factor implicated in epithelial cell differentiation. The GRHL2 motif has been found near activated estrogen receptor (ER) binding sites, and elevated levels of GRHL2 have been linked to worse prognosis in hormone receptor positive breast cancer patients. In its capacity to contribute to a more severe disease state when overexpressed, GRHL2 may function as either a transcription or pioneer factor to aid in the expression of metastasis-associated genes. Our lab previously showed that GRHL2 genomic binding precedes ER binding at co-regulated binding sites. Also, overexpression of GRHL2 in MCF7 cells for 24 hours did not appreciably alter gene expression by RNA-Seq. These data taken together indicate that GRHL2 may be exhibiting pioneer factor activity. However, the specific role of GRHL2 overexpression in hormone positive breast cancer progression remains unknown. In order to examine the mechanism of GRHL2 action, GRHL2 genomic binding was investigated using a tetracycline-inducible MCF7 model that allows controlled overexpression of GRHL2. ChIP studies were performed to determine GRHL2 binding intensity at specific and genome wide GRHL2 binding sites. Specific focus was given to established GRHL2 binding sites near oncogenic genes responsible for epithelial to mesenchymal transition (EMT), dormancy, and proto-oncogenic behavior. A similar analysis examined H3K27 acetylation to validate active gene transcription. An orthogonal technology, Specificity and Affinity for Protein (SNAP) microarrays, which characterizes direct GRHL2 binding to tiled genomic regions identified in ChIP-Seq analyses from multiple labs, was utilized to discriminate direct and indirect GRHL2 binding sites. The requirement for GRHL2 transactivation function in regulation of EMT related genes was further interrogated using transactivation GRHL2 dominant negative mutants. This work aims to distinguish the transcriptional and non-transcriptional activities of GRHL2 in breast cancer cells on a genome wide level and thereby, provide a deeper understanding of how overexpressed GRHL2 contributes to hormone positive breast cancer. Presentation: 6/3/2024

The Impact of the HER2 Status(HER2 Low vs HER2 Negative) on the Pathological Response to Neoadjuvant Chemotherapy in Hormonal Receptor Positive Breast Cancer

Abstract Background More than 50% of breast cancers are currently defined as “Human epidermal growth factor receptor 2 (HER2) low breast cancer (BC)”. Nevertheless, little is known about the response and prognosis of HER2-low BC receiving neoadjuvant chemotherapy (NACT). Aim of the Work The purpose of our study is to evaluate the impact of HER2status (HER2 low vs zero) on the response to neoadjuvant chemotherapy (NACT) in HER2− BC. Patients and Methods This study is a retrospective study that included 96 patients attending the breast clinic at the Clinical Oncology Department, Ain Shams University during the period from 1 January 2020 till 31 December 2022. Results A total of 96 patients were included, of whom 68.8% were HER2 0, where HER2 low was represented by 31.2 % of the patients. HER2 low had similar pCR rates in comparison to HER2 0 (13.3% vs 18.2%, P = 0.55). Ki67 is highly significant correlated with pCR, as in patients who achieved pCR, Ki67 percent was of median 35%, while Ki67 was of median 20% in patients who didn’t achieve pCR (P < 0.01). Conclusion HER2-low status appears to be associated with a similar pCR rate as HER2-0 in HR positive BC patients.

Evaluation of Targetive Axillary Dissection in Node Positive Locally Advanced Breast Cancer Patients with Complete Pathological Response to Neoadjuvant Chemotherapy

Abstract Background This study aimed to evaluate targeted axillary dissection (TAD) in node locally advanced node positive breast cancer patients with complete pathological response to neoadjuvant chemotherapy. Methods This is a prospective cohort study including twenty-five females diagnosed with locally advanced breast cancer with proven lymph node involvement who had complete pathological response to the neoadjuvant chemotherapy regarding the clipped previously involved lymph node. Lymph node biopsy and frozen section of the clipped lymph node after wire localization and the sentinel lymph node after patent blue dye injection was done. This is followed by paraffin section examination of the lymph node biopsy and 6 months follow-up for the patients. Results Twenty-four patients out of twenty-five patients had successful localization of the clipped and sentinel lymph node with no macro-metastasis detected in frozen section. Twenty-two out of the twenty-four patients had no micro-metastasis in paraffin section. Two of the twenty-four patients had micro-metastasis on paraffin section and required axillary radiotherapy. One of the twenty-five patients failed localization of the clipped lymph node and received conventional axillary lymph node dissection. Two patients developed lymphoedema, one of them after axillary radiotherapy and the other one after axillary lymph node dissection. Conclusion The combination of TAD and SLNB can replace Axillary clearance in patients with node positive Locally advanced breast cancer with complete pathological response to neoadjuvant chemotherapy.

Molecular Docking and Pharmacokinetic Profiling of Nab-paclitaxel as Advanced Chemotherapeutic Agent Against HER-2 Positive Breast Cancer Patients.

The main objective of the study is to explore the potential molecular benefits of Nab-paclitaxel as an effective advanced chemotherapeutic agent for HER2-positive breast cancer patients. Specifically, the study aims to assess Nab-paclitaxel as a potential drug candidate for breast cancer treatment. This study used bioinformatics and cheminformatics to analyze the HER2 signaling pathway and its possible interactions with Nab-Paclitaxel. This involves using pharmacokinetic profiling software to evaluate its physicochemical properties, analyzing its potential impact on gene expression modulation, and assessing its binding affinity to the HER2 receptor through molecular docking. The results indicate that the most favorable docking pose occurs between chain B of the HER-2 receptor and Paclitaxel, with a binding energy of -9.4 kcal/mol. Notably, a hydrogen bond is observed in ARG849, with 3.0 Angstrom (Å). Previous research highlights Paclitaxel's impact on breast cancer patients' genes, particularly the ABCB1 gene responsible for P-glycoprotein production, contributing to drug resistance in chemotherapy. Nab-paclitaxel exhibits potential ease of metabolism, as it minimally inhibits drug-metabolizing cytochrome P450 enzymes. Additionally, despite initial concerns related to drug-likeness parameters and molecular weight discrepancies, the pharmacokinetic profile of Nab-Paclitaxel suggests improvements in delivery facilitated by an albumin-supported nanoparticle delivery mechanism. The binding energy confirms the secure docking of ligands to receptors, suggesting the stability of the interaction between them. Nevertheless, prolonged administration of Paclitaxel poses the risk of inducing drug resistance, a significant factor contributing to treatment failure. This emphasizes the need to explore new candidate drug combinations or identify alternative drug-binding interaction sites. Such endeavors hold the potential to enhance the effectiveness of drug treatments and address challenges associated with prolonged Paclitaxel use.

Inetetamab combined with sirolimus and chemotherapy for the treatment of HER2‐positive metastatic breast cancer patients with abnormal activation of the PI3K/Akt/mTOR pathway after trastuzumab treatment

AbstractBackgroundWe explored the efficacy and safety of inetetamab combined with sirolimus and chemotherapy for the treatment of human epidermal factor receptor 2 (HER2)‐positive metastatic breast cancer patients with abnormal activation of the PI3K/Akt/mTOR (PAM) pathway after trastuzumab treatment.MethodsFor this prospective multicenter clinical study, HER2‐positive metastatic breast cancer patients with PAM pathway mutations confirmed by histology or peripheral blood genetic testing were enrolled from July 2021 to September 2022. Patients were randomly assigned to a trial or control group. The patients in the trial group received inetetamab combined with sirolimus and chemotherapy, while the control group patients received pyrotinib and chemotherapy. The RECIST v1.1 standard was used to evaluate efficacy. Descriptive statistics were used to summarize the clinicopathological features, and the Kaplan–Meier method was used to generate survival curves. The log‐rank test was used to compare progression‐free survival (PFS) between the two groups.ResultsA total of 59 HER2‐positive metastatic breast cancer patients with abnormal activation of the PAM pathway were included, of which 37 received inetetamab combined with sirolimus and chemotherapy treatment and 22 received pyrotinib and chemotherapy treatment. The median PFS was 4.64 months in the inetetamab group and 5.69 months in the pyrotinib group, with no statistically significant difference (p = 0.507). The objective response rates were 27.3% for the inetetamab group and 29.4% for the pyrotinib group. The safety assessment indicated that the adverse event (AE) incidences were 86.1% (31/36) in the inetetamab group and 78.9 (15/19) in the pyrotinib group, with 9 (25%) and four (21.1%) Grade 3/4 AEs in the inetetamab and pyrotinib groups, respectively.ConclusionsFor metastatic HER2‐positive breast cancer patients with abnormal PAM pathway activation and previous trastuzumab treatment, the combination of inetetamab with sirolimus and chemotherapy is equivalent to the combination of pyrotinib and chemotherapy. Therefore, this regimen could be a treatment option for PAM pathway‐activated metastatic HER2‐positive breast cancer patients.

Predictors of pathological complete response to neoadjuvant treatment in invasive breast cancer with different human epidermal growth factor receptor 2 (HER2) subcategories.

Among human epidermal growth factor receptor 2 (HER2)-positive breast cancer patients who receive anti-HER2 treatment, a noteworthy correlation between pathological complete response (pCR) and longer survival has been observed. The rate of pCR varies with the tumor's degree of HER2 protein expression. The aim of this study was to assess the correlations between clinicopathological characteristics, magnetic resonance imaging (MRI) parameters, and pCR in breast cancer with different HER2 subcategories. A total of 281 invasive breast cancer patients diagnosed with HER2-positivity were included. HER2-positive translated to immunohistochemistry (IHC) 3+ or IHC 2+/fluorescence in situ hybridization (FISH)(+). All enrolled patients underwent baseline MRI examination and received neoadjuvant chemotherapy, dual anti-HER2 therapy, and subsequent therapeutic surgery from January 2021 to May 2022. A logistic regression model was used to evaluate the effects of covariates on pCR. Compared to the IHC 2+/FISH(+) group, patients with IHC 3+ tumors had a higher pCR rate (58.1% vs. 26.7%, P<0.001), clinical stage (58.6% vs. 40%, P=0.038), apparent diffusion coefficient (ADC) value (0.96 vs. 0.88 mm2/s, P=0.004), and were more likely to be estrogen receptor (ER) negative (55.9% vs. 31.1%, P=0.002) and progesterone receptor (PR) negative (72.5% vs. 46.7%, P=0.001). In both groups, univariate analysis showed that the pCR group more often had ER-negative and PR-negative status than the non-pCR group (P<0.001). The final multivariable analysis showed that ER-negativity was associated with pCR in the IHC 2+/FISH(+) group (P=0.004). ER-negativity and the longest diameter were two independent predictors of pCR in the IHC 3+ group (P<0.001 for ER, P=0.026 for longest diameter). The IHC 3+ group had a higher pCR rate than the IHC 2+/FISH(+) group. Along with clinicopathological characteristics, MRI parameters were supplemental predictors of pCR, particularly in IHC 3+ patients.

Possible protective effect of rosuvastatin in chemotherapy-induced cardiotoxicity in HER2 positive breast cancer patients: a randomized controlled trial

Cardiotoxicity is a side effect of chemotherapy in human epidermal growth factor receptor 2 (HER2) positive breast cancer patients receiving both anthracyclines and trastuzumab. We looked for a possible protective effect of rosuvastatin against chemotherapy-induced cardiotoxicity. Methods: 50 newly diagnosed HER2 positive breast cancer patients were randomly allocated into two groups: 25patients in each. Group 1(control group) received doxorubicin for 4 cycles (3 months) followed by trastuzumab adjuvant therapy. Group 2 (treatment group) received doxorubicin for 4 cycles (3 months) followed by trastuzumab adjuvant therapy and 20 mg of oral rosuvastatin 24 h before the first cycle of chemotherapy and once daily for the rest of the follow-up period (6 months). Transthoracic echocardiography was done, and blood samples were collected for patients 24 h before the initiation of therapy, after 3 months and after 6 months to assess serum levels of high sensitivity cardiac troponin I (hs-cTnI), Myeloperoxidase (MPO), Interleukin-6 (IL-6) and Alanine aminotransferase (ALT). The study was retrospectively registered in Clinical Trials.gov in April 2022. Its ID is NCT05338723. Compared to control group, Rosuvastatin-treated group had a significantly lower decline in LVEF after 3 months and after 6 months. They had significantly lower Hs-cTnI and IL-6 after 3 months and after 6 months, and significantly lower MPO after 6 months. Four patients in control group experienced cardiotoxicity while no one in rosuvastatin-treated group. Rosuvastatin attenuated cardiotoxicity, so it is a promising protective agent against chemotherapy-induced cardiotoxicity.

Breast Cancer Adjuvant Radiotherapy in Up-Front to Chemotherapy: Is There a Worthwhile Benefit? A Preliminary Report.

We administered a new breast cancer (BC) adjuvant therapy sequence that delivered postoperative radiotherapy (PORT) before chemotherapy (CT). Our aim was to assess the gain in time to start PORT and the G2-G3 acute-subacute toxicity rate of whole breast adjuvant hypofractionated radiotherapy (AH-RT) administered up-front to the third-generation adjuvant CT (A-CT) in high-risk nodal positive BC in a preliminary report at 2 years. This retrospective study analysed the duration of treatment and safety of AH-RT administered up-front to A-CT in high-risk nodal positive BC patients (pts). Data on 45 pts treated between 2022-2023 were collected. All pts underwent the third-generation A-CT after AH-RT 15-5 fractions with or without a boost. Acute toxicity was scored according to CTCAE v5.0 for skin, pulmonary, and cardiac adverse events. Univariate and multivariate analyses were conducted to assess significant prognosticators for skin/lung/heart acute toxicities in the AH-RT 5-15 fractions arms and CT (p < 0.005). A reduction in the time to PORT initiation and overall adjuvant treatment time was recorded. RT was initiated 5 median weeks after surgery, and A-CT was performed 9 median weeks after surgery. The median duration of the entire adjuvant treatment was 35 weeks after surgery. At 6 months mean follow-up, no significant differences in G2-G3 toxicity were noted between the different hypofractionated RT arms, irrespective of the CT schedules, irradiated volumes, or boost (SIB or sequential) in univariate and multivariate analyses. In the multivariate analysis, no significant effects in CT schedules and AH-RT 5-15 arms for skin/lung acute toxicities (p = 0.077 and p = 0.68; 0.67 and 0.87, respectively) were recorded. As a new PORT approach in BC, AH-RT up-front to the third-generation A-CT appeared safe with a low acute toxicity profile, providing an advantage in shortening the time from surgery to PORT initiation and the overall adjuvant treatment time.

Pathological complete response rate to anthracycline versus non−anthracycline based chemotherapy regimens in localized and regional HER2 neu positive breast cancer.

e12632 Background: Debate over the need of anthracycline as part of neoadjuvant chemotherapy in HER2-neu early breast cancer was addressed in many trials with results favoring similar outcomes with or without anthracycline. This was not adopted fully in Saudi Arabia because of concern regarding ethnic differences in response to treatment. We conducted this retrospective analysis to evaluate if there is any difference in pathological complete response rate (PCR) in patients with early HER2-neu positive breast cancer depending on neoadjuvant chemotherapy regimen. Methods: Patients with HER2-neu positive early breast cancer who were treated with neoadjuvant chemotherapy at Johns Hopkins Aramco Healthcare (JHAH) facility between the year 2018 and 2022 were all evaluated for pathological subtype, HER2-neu status and type of neoadjuvant chemotherapy administered. Pathological response status was evaluated in all patients and PCR was measured to see if there was any difference depending on the use of anthracycline (AC) or non-anthracycline (non-AC) based chemotherapy regimen. Patient demographics, tumor characteristics, clinical stage, treatments and outcomes were collected via JHAH’s oncology registry. Categorical variables are reported as frequencies and percentages. The association between chemotherapy regimen AC vs non-AC based and PCR was analyzed using Fisher Exact Test. p-value &lt;0.05 was considered statistically significant. Analyses were conducted using JMP version 15. Results: In this study 59 HER2-neu positive early breast cancer patients were identified. We examined their clinical characteristics and treatment outcomes. Median age was 57. The most prevalent histology was invasive carcinoma of no special type (79.66%), Estrogen receptor positivity was observed in 72.88% of patients, while progesterone receptor positivity was seen in 62.71% of cases. Majority of patients were alive (96.61%) at the time of data collection. There was no significant difference in clinical stage in both groups. The association between chemotherapy type and pathological response was assessed. Among patients receiving AC chemotherapy (n=29), 55.17% achieved PCR, while for patients receiving Non-AC chemotherapy (n=30), the PCR rate was 50%. However, this difference was not statistically significant (p-value = 0.8). Conclusions: In our cohort of HER-neu positive early breast cancer patients who received neoadjuvant therapy there seems to be no significant difference in PCR with AC or Non-AC based chemotherapy regimens. This is concordant with the international trends.

The predictive role of Ki67 in pathological complete response (pCR) and invasive disease-free survival (IDFS) in HER2-positive breast cancer: A retrospective study of 246 cases.

e12610 Background: While Ki67 is a routine diagnostic measure for early hormone receptor positive breast cancer, it is not integrated into the standard procedure for patients with Human Epidermal Growth Factor Receptor 2 (HER2)-positive breast cancer patients, given the substantial risk linked to HER2 expression alone. Consequently, the predictive significance of Ki67 in achieving pathological complete response (pCR) or invasive disease-free survival (IDFS) in this subgroup remains uncertain. Methods: This retrospective, bi-centric analysis focused on HER2-positive early breast cancer patients undergoing neoadjuvant chemotherapy from 2015 to 2023. We assessed the correlation between Ki67 values and the achievement of pathological complete response (pCR, defined as ypT0/is, pN0). Multivariable logistic regression analyzed the independent association of various clinical parameters, including Ki67, with pCR. Ki67 values were categorized into risk groups (low &lt;15%, intermediate 15.1-35%, high &gt;35%) following the GepardTrio data [1]. Kaplan-Meier estimator calculated differences in overall and invasive disease-free survival. Results: The study included 246 HER2-positive early breast cancer patients with known Ki67 expression, followed for a median of 42 months. The median age was 52 years. Final nodal status was pN0 in 80.5%, pN1 in 15%, and pN2 in 3.3%. Hormone receptor positivity was observed in 66% of patients. 147 patients (60%) achieved pCR. Median Ki67 was 30. When categorized, 13% were low, 41.5% intermediate, and 45.5% high risk. No correlation between Ki67 and pCR was observed (p=0.25). HER2 IHC score 3+ significantly increased pCR compared to IHC 2+ (62.2% vs. 44.6%, p=0.023). Hormone receptor-positive tumors had a lower pCR rate (52.7% vs. 72.4%, p=0.0016. 5-year overall survival was 96.5% for pCR and 83.8% for non-pCR (p=0.008). 5-year invasive disease-free survival showed no difference between low Ki67 (89.5%), intermediate Ki67 (79.9%), and high Ki67 (80.9%) groups (p=0.77). Conclusions: In this study, Ki67 did not predict pCR in HER2-positive breast cancer, providing no additional clinical value. HER2 IHC score and hormone receptor status were predictive indicators for pCR. Ki67 expression appears to lack additional value in HER2-positive breast cancer, considering resource implications. 1. Denkert C et al: Ann Oncol. 2013 Nov;24(11):2786-93. doi: 10.1093/annonc/mdt350. Epub 2013 Aug 22. PMID: 23970015.

Use of Oncotype vs. Breast Cancer Index (BCI) for extended endocrine therapy decisions: A single center analysis in stage IA hormone receptor positive breast cancer.

e13083 Background: Extended Endocrine Therapy (EET) for hormone receptor positive HER-2 negative early-stage breast cancer reduces late recurrence risks but raises concerns about toxicity. Biomarker tests like the Breast Cancer Index (BCI) are vital for identifying patients who could benefit from continued ET, reassuring others against unnecessary extension. This study evaluates prognostic implications for both Oncotype Dx (Recurrence score, RS) and BCI amidst concerns about added testing costs in patients with early stage, estrogen receptor (ER) positive breast cancer. Methods: This is a single institution retrospective review of Stage IA ER positive HER-2 negative breast cancer patients who underwent both Oncotype Dx and BCI testing from January 2021 to December 2023. Pearson's correlation coefficient (r) was used to assess the linear relationship between the assays (p&lt;0.05 for significance), analysis was performed with SAS software, version 9.4. Results: Fifty-eight patients with Stage IA ER positive HER-2 negative breast cancer who had both Oncotype and BCI results were identified (100% female; mean age 72.2 years [54-87]). After a median followed up of 72 months (63-75), no systemic or locoregional recurrences were reported. A low positive correlation between Oncotype and BCI was observed across the entire cohort (r=0.4058; p=0.0016). However, subgroup analysis showed no significant correlations: Oncotype &lt;11 (n=17; r=0.2415; p=0.3504), Oncotype ≤18 (n=43; r=0.0914; p=0.5600), Oncotype &lt;26 (n=51; r=0.2530; p=0.0733); Oncotype ≥26 (n=7; r=-0.5634; p=0.1878). Correlation was also not found in patients with Grade 1 tumor (n=16; r=0.3138; p=0.2365). Thirty-nine patients (67.24%) had their treatment recommendation changed based on BCI results. Side effects from ET affected 15 patients (25.86%) and included arthralgias (60%, n=9), hot flashes (26.67%, n=4), depression (13.33%, n=2), insomnia (6.67%, n=1), and others (53.3%, n=8). Twenty-two patients (37.93%) developed new osteopenia, and 6 (10.34%) new osteoporosis while on EET. Eight patients (13.79%) had ET interruption during their treatment course. Conclusions: Despite inclination towards cost-saving measures, Oncotype DX may be more useful to give prognosis in the early adjuvant period whereas BCI is more useful to evaluate late recurrence risk. Low or high Oncotype scores and tumor grade may not align with BCI findings. Considering the importance of managing toxicity against the risk of late recurrence, incorporating BCI testing can enhance EET recommendations, even for Stage I, node-negative, ER positive patients.

Prognostic and Predictive Significance of HER2-low Expression in Metastatic Hormone Receptor Positive Breast Cancer Patients Receiving CDK4-6 Inhibitor Therapy

Objective: This study aimed to analyze the predictive and prognostic value of HER2-low expression in hormone receptor (HR) positive human epidermal growth factor receptor-2 (HER2) negative metastatic breast cancer patients receiving cyclin-dependent kinase-4/6 inhibitor (CDK4/6i) therapy. Methods: This retrospective study included patients who received CDK4/6i plus endocrine therapy (ET). The pathological and clinical characteristics and survival times of the patients were compared and analyzed. Results: Our study included 122 patients. There were HER2-zero 88(72%) and HER2-low 34 (28%) patients. The median progression free survival (mPFS) of all patients who received CDK4/6i+ET was 21 (95% confidence interval (CI),18.5–23.5) months, while mPFS was not reached in the HER2-zero group, and mPFS in the HER2-low group was 12 (95%CI, 6.8–17.1) months (p=0.001). The mPFS was shorter in patients with primary endocrine resistance (6 vs. 21 months, p=0.001). There was a change in the HER2-low status of 26(45%) patients with recurrence compared to the first biopsy. In the HER2-zero and HER2-low groups, 22(25%) and 24(71%) patients, respectively, progressed with CDK4/6i+ET (p=0.001). Estrogen receptor (ER) levels less than and greater than 50% resulted different mPFS (6 and 21 months, respectively) (p=0.025). Median PFS differed based on CDK4/6i+ET combination, treatment line, and best treatment response (all p=0.001). In multivariate analysis, HER2 status(p=0.018), chemotherapy status(p=0.006), best response status with CDK4/6i (p=0.001) for PFS, and best response status with CDK4/6i therapy (p=0.007) for OS were significant. Conclusions: In patients with HR+HER- metastatic breast cancer receiving CDK4/6i therapy, the duration of mPFS was lower in the HER2-low group than that in the HER2-zero group. HER2-low expression is a predictive biomarker of response to CDK4/6 inhibitor therapy.

Efficacy and Satisfaction among HER2 Positive Breast Cancer Patients Undergoing Subcutaneous Injection of PHESGO along with Chemotherapy: A Case Series

Background: The prevalence of Human Epidermal Growth Factor Receptor 2 positive (HER2+) breast cancer (BC) in India ranged from 11% to 17%. A combination of intravenous (IV) pertuzumab, trastuzumab and docetaxel in HER2+ BC reported a significant increase in the overall survival rate. However, the time taken for infusion of these drugs is lengthy. PHESGO, a combination of these two drugs along with hyaluronidase is provided subcutaneously and the time taken is 5-8 minutes. Despite patient preference for PHESGO, its efficacy and satisfaction levels in the Indian context remain unexplored. This case series investigates the efficacy of PHESGO with chemotherapy and assesses the level of satisfaction reported by HER2+ BC patients. Methods: HER2+ BC patients were identified retrospectively from January 2022 to November 2023. Interviews during follow-ups assessed patient satisfaction. Efficacy was evaluated based on Positron Emission Tomography (PET) scans for metastatic/adjuvant settings and pathological complete response (pCR) rate for neoadjuvant cases. Results: In total 27 HER2+ BC patients received PHESGO treatment with a median age of 54.5 years. Patients who received PHESGO with chemotherapy in neoadjuvant and metastatic settings were 44.4% and 51.9% respectively. The median cycle of PHESGO with chemotherapy was 5. Neoadjuvant patients showed an 83.3% pCR rate, while 85.7% of metastatic patients reported partial response after three cycles. Among 25 patients, 92% were satisfied with subcutaneous administration of PHESGO. Conclusion: The findings support the potential of PHESGO as an effective and convenient treatment option for HER2+ BC patients. However, further research, including larger prospective studies and long-term follow-ups, is warranted to comprehensively evaluate the safety profile, quality of life, and comparative effectiveness of PHESGO versus intravenous administration.

Left ventricular global longitudinal strain is worse in BRCA mutation positive breast cancer patients prior to cancer treatment and premature menopause.

Breast cancer patients with mutations in human tumor suppressor genes BRCA1 and BRCA2 are at higher risk of cardiovascular disease (CVD) than the general population, as they are frequently exposed to cardiotoxic chemotherapy, anti-estrogen therapy, radiation, and/or oophorectomy for cancer-related treatment and prophylaxis. Animal and cell culture models suggest that BRCA mutations may play an independent role in heart failure. We sought to evaluate cardiac structure and function in female BRCA1 and BRCA2 mutation carriers with breast cancer compared to BRCA wildtype women with breast cancer. We performed a 1:2 age- and hypertension-matched retrospective cohort study comparing BRCA1 and BRCA2 mutation carriers (n = 38) versus BRCA wildtype controls (n = 76) with a new diagnosis of breast cancer. Echocardiographic data were obtained within 6months of breast cancer diagnosis and prior to chemotherapy, anti-estrogen therapy, radiation, or oophorectomy. Left ventricular global longitudinal strain (LV-GLS), a highly sensitive marker of LV function, was measured using QLab 15 (Philips Healthcare). In the total cohort of 114 patients with a new diagnosis of breast cancer, the median age was 45 ± 11years and the prevalence of hypertension was 8%. There were no differences in traditional cardiovascular disease risk factors between cases and controls. BRCA carriers had lower LV-GLS (-18.1% ± 4.7% vs. -20.1% ± 3.8%, p = 0.02) and greater right atrial area (12.9cm2 ± 2.7cm2 vs. 11.8cm2 ± 2.0cm2, p = 0.04) compared to controls; however, both LV-GLS and right atrial area were within the normal range. Compared to controls, BRCA carriers had a trend toward worse LV posterior wall thickness (0.89cm ± 0.15cm vs. 0.83cm ± 0.16cm, p = 0.06) although not statistically significant. In women with newly diagnosed breast cancer and prior to treatment, LV-GLS was worse in BRCA1 and BRCA2 mutation carriers compared to those with BRCA wildtype. These findings suggest that BRCA mutations may be associated with subtle changes in cardiac function. Whether differences in GLS translate to increased cardiovascular risk in women with BRCA mutations needs to be further characterized.

Abstract PO5-04-01: Inetetamab combined with sirolimus and chemotherapy in HER2 positive metastatic breast cancer patients with abnormal activation of Pi3k/Akt/mTOR pathway after trastuzumab treatment

Abstract Objective: To explore the efficacy and safety of Inetetamab Combined with Sirolimus and Chemotherapy in the treatment of human epidermal factor receptor 2 (HER2) positive metastatic breast cancer patients with abnormal activation of Pi3k/Akt/mTOR (PAM) pathway after Trastuzumab treatment. Methods: This prospective multicenter clinical study enrolled HER2 positive metastatic breast cancer patients at the National Cancer Center in China from July 2021 to September 2022 with PAM pathway mutation confirmed by histology or peripheral blood genetic testing. The inclusion criteria included: 1) Recurrent and metastatic breast cancer patients with HER2 positive confirmed histologically; 2) ECOG PS score ≤ 2; 3) Patients who have progressed after previous treatment with Trastuzumab; 4) Patients with PAM pathway mutation confirmed by Genetic testing; 5) Patients' cardiac, pulmonary, liver and bone marrow functions are basically normal; 6) Patients voluntarily sign informed consent forms. The exclusion criteria included: 1) Patients previously treated with mTOR inhibitors or pyrotinib; 2) Patients who have used chronic Corticosteroid for more than 3 months or used Immunosuppressive drug within 4 weeks; 3) Patients with symptomatic central nervous system metastasis; 4) Patients with left ventricular Ejection fraction&amp;lt; 50% or clinical manifestations of obvious arrhythmia, myocardial ischemia, severe atrioventricular block, cardiac insufficiency, and severe valvular disease; 5)Diagnosed with other malignant tumors within five years. Patients were randomly divided into trial group and control group. The patients in the trial group received inetetamab combined with sirolimus and chemotherapy, and control group received pyrotinib and chemotherapy. RECISTv1.1 standard was used to evaluate the efficacy of patients. Descriptive statistics are used to summarize clinical pathological features. Kaplan Meier method was used to draw survival curves. Log-rank test was used to compare progression free survival (PFS) differences between groups. P&amp;lt; 0.05 was considered statistically significant. Results:A total of 59 HER2 positive metastatic breast cancer patients with abnormal activation of PAM pathway were included, of which 37 patients received the treatment of inetetamab group and 22 patients received the treatment of pyrotinib group. The median follow-up time was 5.33 months. In the intent-to-treat set, the median PFS of patients in the inetetamab group was 4.64 months, which was shorter than 5.69 months in the pyrotinib group. There was no statistically significant difference between the two groups (P=0.51; HR=0.41; 95% CI, 0.12-1.45). The objective response rate (ORR) of the inetetamab group and the pyrotinib group were 28.1% and 29.4%, respectively. In terms of safety, the incidence of adverse events (AE) in the experimental group was (33/37) 89.1%, while (16/21) 76.2% in the control group. The incidence of AE above level 3 in the inetetamab group and pyrotinib group were (13/37) 35.1% and (3/21) 14.3%, respectively. Conclusion:For the metastatic HER2 positive breast cancer patients with abnormal activation of PAM pathway treated with trastuzumab previously, the combination of inetetamab with sirolimus and chemotherapy regimen are equivalent to the combination of pyrotinib and chemotherapy regimen. It demonstrated that combination of inetetamab with sirolimus and chemotherapy could be one of the treatment options for the metastatic HER2 positive breast cancer patients. Citation Format: Qiao Li, Dan Lv, Xiaoying Sun, Mengyuan Wang, Li Cai, Feng Liu, Chenghui Li, Jiuda Zhao, Jing Sun, Yehui Shi, Fei Ma. Inetetamab combined with sirolimus and chemotherapy in HER2 positive metastatic breast cancer patients with abnormal activation of Pi3k/Akt/mTOR pathway after trastuzumab treatment [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 PO5-04-01.

Abstract PO3-23-07: Evaluation of the role of axillary ultrasound to estimate axillary nodal burden to guide de-escalation of upfront axillary surgery in node positive early breast cancer patients

Abstract Background: Axillary surgery is now routinely de-escalated in clinically node negative breast cancer patients with limited axillary nodal burden (up to 2 involved sentinel nodes) based on the results of ACOSOG-Z0011 and AMAROS trials. However, patients with proven axillary metastasis following on ultrasound (AUS) guided core needle biopsy (CNB), undergoing primary surgery are still subjected to an axillary lymph node dissection (ALND) irrespective of the magnitude of the axillary nodal burden. If we could predict axillary nodal burden with a low false negative rate (FNR) for the presence of extensive axillary nodal involvement, we can then hypothesize that axillary surgery could be safely de-escalated in this cohort of patients. We investigated whether pre-operative AUS suggesting limited axillary burden is sensitive enough to rule out gross axillary disease burden. Methods: A single institution retrospective study. We undertook an electronic chart review of all T1 to T3 patients undergoing upfront ALND with either mastectomy or breast conserving surgery between January 2019 and June 2023. Patients with palpable axillary nodes, locally advanced breast cancer or a completion ALND after positive sentinel lymph node biopsy (SLNB) were excluded from the study. Clinical and pathological characteristics associated with nodal burden of disease were evaluated. Limited axillary burden was defined as &amp;lt; 2 involved nodes with ≥3 taken as gross nodal burden for primary analyses. Sensitivity analyses were carried out with limited axillary burden defined as &amp;lt; 3 involved nodes (N1) and ≥4 (N2) taken as gross nodal burden. Subgroup analyses in T1 or T2 tumors were carried out as well. The probabilities of discordant events, defined as limited burden on AUS-CNB but gross burden on final histopathology evaluation (HPE), assuming 10% FNR, were estimated using inverse cumulative binomial distribution function. Results: Data on the exact number of suspicious nodes on AUS were missing for 2 patients, therefore, the final study cohort included 39 patients. The correlation between AUS nodal burden and that on HPE was moderate (Spearman’s rho = 0.48; p = 0.0018). The sensitivity and specificity of AUS in identifying gross nodal burden were 61% and 81% respectively. Observation of 9 discordant events in 22 patients with low burden on AUS ruled out an FNR of &amp;lt; 10% with 99.99% certainty. The sensitivity and specificity in T1/T2 subgroup were 60% and 75% respectively. The sensitivity analyses classifying N1 as limited and N2 as gross axillary burden showed the sensitivity and specificity of 35% and 82% respectively and an FNR of &amp;lt; 10% was ruled out with 99.996% certainty. Conclusion: Pre-operative AUS alone lacks the sensitivity and specificity to accurately predict the true axillary nodal burden to safely guide de-escalation of axillary surgery. AUS followed by targeted axillary dissection (TAD) in conjunction with a dual technique SLNB may provide the desired sensitivity and specificity to guide de-escalation of axillary surgery. A prospective evaluation of this approach is merited. Given the limited number of patients that could be enrolled in such prospective study from individual institutions, an international collaborative effort is needed to address this important research question. Citation Format: Nidhi Garg, Mangesh Thorat, Hisham Hamed, Ashutosh Kothari. Evaluation of the role of axillary ultrasound to estimate axillary nodal burden to guide de-escalation of upfront axillary surgery in node positive early breast cancer patients [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 PO3-23-07.

Abstract PO3-22-03: Effect of Radiation Therapy on Survival Outcomes in Elderly ER/PR Positive AJCC Stage T1 Breast Cancer Patients

Abstract Background: The CALGB 9343 study in 2004 reported that women &amp;gt;70 years of age with pT1NO hormone receptor positive breast cancer received no meaningful benefit from breast irradiation following lumpectomy. The effectiveness of adjuvant radiation therapy in node negative, T1 tumor patients has been limited to institutional experiences with relatively lack of information in population-based studies. In this hospital-based study using National Cancer Data Base (NCDB) from 2004 to 2020, we report on adjuvant radiation therapy (XRT) usage and the survival outcomes in stage IA, IB, IC breast cancer patients who received XRT versus those who did not. Materials and Methods: Patients in the National Cancer Database (NCDB) who were registered between 2004 and 2019 and followed up to the end of 2020 were used in this research. We evaluated a cohort of 126,156 female breast cancer patients of age &amp;gt;= 70 years with the American Joint Committee on Cancer (AJCC) stage TIA, TIB, and TIC. All patients were ER/PR positive, received hormonal therapy, all patients were either white or black, were either privately or Medicare insured, received hormonal therapy, and patients were receipt of adjuvant chemotherapy or not. Radiation statuses were grouped as no radiation, radiation only and/or radiation with boost. Other adjusted variables included: age, race, Charlson comorbidity index, payer status, income, education, distance traveled, diagnosing/treating facility, location of treatment and treatment delay. SAS for Windows 9.4 was used for all data management and statistical analysis. Multivariate Cox regression was used to assess the effect of the XRT on overall survival while adjusting for other factors. All p-values &amp;lt; 0.05 or 95% Confidence Limits of Hazards Ratio (HR) does not include 1 were considered statistically significant. Results: Among 126,156 female breast cancer patients, the age distribution was 47.87%, 31.72%, and 20.4% for age group of 70-74, 75-79, 80 or older, respectively. Ninety-three percent of patients were white. 89% of patients were Medicare and 11% were privately insured at diagnosis. 21% of patient were with the Charlson Comorbidity index score 1 or above. 10.77%, 34.42% and 54.81% of patients were AJCC Stage T1A, T1B, and T1C respectively. 11.7% of patients received chemotherapy and 57.9% of patients received radiation therapy. 54.38%, 59.59%, and 57.59% of T1a, T1b, and T1c patients received the XRT, respectively. In univariate analysis, the XRT demonstrated a statistically significant increase of 10-year survival by 9.75%, 9.8%, and 12.6% in T1a, T1b, and T1c (all p &amp;lt; 0.0001) patients respectfully. In multivariate cox regression analysis, age was a predictor of survival outcome with a HR at 1.65, 3.02 for 75-79, and 80 or older as compared to 70-74 years old, respectively. In addition, compared to patients who traveled less than 20 miles, the HR were 0.90 for patients travelled more than 20 miles. AJCC stage was also associated the survival, a HR of 1.05 (95% CI: 1.01-1.186) for T1b, 1.16 (95% CI: 1.11 – 1.21) for T1c as compared for T1a. Adjusting for other factors, the usage of radiation reduced the risk of dying by 25% (HR=0.75, 95% CI: 0.73-0.77) when compared to no radiation therapy. Conclusion: The current study has demonstrated that more than 54% of these patients received radiation therapy. In univariate analysis, the benefit of adjuvant radiation therapy is more than 9.7% for T1a, T1b, and T1c on 10-year overall survival which is statistically significant. Adjusting for other factors, patients receiving radiation therapy in these elderly population have a 25% less chance of dying as compared to no radiation therapy regardless of AJCC Stage. A further propensity score matching method would help assess the effectiveness of radiation therapy on these patients’ population. A randomized prospective clinical trial would be better to define the precise benefit of adjuvant radiation therapy in this elderly population. Table 1 Patients Demographic, Social Economic and Clinical Characteristics XX- XX Table 3 Hazard Ratios estimate from Multivariate Cox Regression XX- XX Radiation Effect on Overall Survival of Elderly Breast Cancer Patients by Stage T1A, T1B, T1C XX- XX Citation Format: Runhua Shi, Gary Burton. Effect of Radiation Therapy on Survival Outcomes in Elderly ER/PR Positive AJCC Stage T1 Breast Cancer Patients [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 PO3-22-03.

Abstract PO4-04-10: Selection criteria for second-line treatments after Cyclin-dependent kinase 4/6 inhibitors failure in Hormone Receptor positive metastatic breast cancer patients: the preliminary experience of the HERMIONE-13 trial

Abstract BACKGROUND: Cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) represent the standard of care for hormone receptor-positive (HR+)/Human Epidermal Growth Factor 2 negative (HER2-) metastatic breast cancer (MBC); no consensus actually exists for second-line (2L) treatments. The HERMIONE-13 trial evaluates the adopted therapeutic options after CDK4/6i failure and the potential factors that influence these choices. METHODS: HERMIONE-13 is a retrospective and prospective multicentric observational trial involving 15 Italian Centers. Information about therapies after disease progression to CDK4/6i from January 2016 until December 2020 was collected for the present analysis, aiming at evaluating which are the clinical criteria guiding the choice of 2L therapy after CDK4/6i failure. RESULTS: 114 pts have been enrolled: 14 pts (12.3%) received neoadjuvant treatment, 80 (70.2%) adjuvant therapy, of whom 46 (57.5%) chemotherapy (CT)+ endocrine therapy (ET) and 33 (41.3%) ET alone. Among the 79 pts treated with adjuvant ET, 44 pts (55.7%) showed primary or secondary endocrine resistance. 39 pts (34.2%) received first-line (1L) CDK 4/6i in combination with Fulvestrant (F), the remaining with aromatase inhibitors (AIs). Median duration of 1L CDK4-6i was 10.4 months (interquartile range (IQR) 4.7-17.4). Median age at 2L start was 59.5 years (IQR 51-68). As 2L therapy, 79 pts (69.3%) received CT±targeted therapy (TT) and 35 (30.7%) ET±TT. Visceral metastases at the beginning of 2L were documented in 46 pts (40.4%). Comorbidities were present in 48 (42.9%) of the pts, mainly cardiac diseases (25, 22.3%); 71 pts (63.4%) showed a 1L-related adverse events (AEs) (NA: 2 pts), mainly hematological toxicity (60, 53.6%). Among 79 pts treated with adjuvant ET, 60 (76%) were addressed to 2L CT±TT, while 19 (24%) to an ET-based therapy. A longer duration of 1L was observed in pts treated with 2L ET±TT (12.5 months, 7.2-22.2) in comparison with those treated with CT±TT (8.7 months, 4.2-14.9). The majority of pts treated with 1L F+CDK 4/6i underwent 2L CT-based treatment, as summarized in Table 1. Analyzing the population treated with 2L CT±TT, we observed that median age was 58 years (49-67), slightly lower than that of pts treated with ET±TT (63, 54-69). Among pts with visceral metastases, 30 pts (65.2%) were addressed to 2L CT±TT and 16 pts (34.8%) to ET±TT; CT±TT was also the favorite choice for the majority of pts with concomitant disease (33, 68.8%) and with previous CDK4/6i-related toxicity (47, 66.2%). Among age, visceral metastases, comorbidities, adjuvant treatment, duration of 1L therapy, use of 1L F and 1L related AEs, univariate analysis revealed that previous use of adjuvant ET (p=0.021), 1L F (p&amp;lt; 0.001), duration of 1L treatment (p=0.043) and age at 2L start (p=0.053) are all factors influencing the choice of 2L therapy. At the multivariate logistic regression model, only the use of F in association with CDK4/6i as 1L treatment and age at 2L therapy were associated with the choice between ET±TT vs CT± TT, with a backward selection, as summarized in table 2. CONCLUSION: The preliminary results of our study suggest that previous F in combination with CDK4/6i is a statistically confirmed predictor of choice for subsequent CT, whereas the increase in age is significantly associated with the choice for ET. Further research is needed to investigate the optimal sequencing of treatments following CDK4/6i and to determine predictive factors of response to 2L therapies. Table 1 2L choices in 1L F+CDK 4/6i pts. Table 2 Statistical model with the significant variables. Citation Format: Marina Elena Cazzaniga, Emanuela Rossi, Antonella Turla, Massimo Ambroggi, Alice Baggi, Rossana Berardi, Fulvio Borella, Serena Capici, Federica Cicchiello, Luigi Coltelli, Ugo De Giorgi, Antonella Ferro, Ornella Garrone, Monica Giordano, Elisabetta Landucci, Marco Mazzotta, Gabriella Moretti, Raffaella Palumbo, Francesca Fulvia Pepe, Patrizia Vici, Fable Zustovich, Viola Cogliati. Selection criteria for second-line treatments after Cyclin-dependent kinase 4/6 inhibitors failure in Hormone Receptor positive metastatic breast cancer patients: the preliminary experience of the HERMIONE-13 trial [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 PO4-04-10.

Abstract PO3-12-06: The pilot study for a mobile-based monitoring solution to manage menopausal symptoms of premenopausal breast cancer patients with endocrine therapy

Abstract Background Endocrine therapy (ET) is the most important treatment for hormone receptor (HR)-positive breast cancer (BC) patients. Each of the endocrine medications, such as aromatase inhibitors (AIs), luteinizing hormone-releasing hormone (LHRH) analogs, and selective estrogen receptor modulators, has its own set of side effects, and these might lead to poor drug adherence and eventual discontinuation. There are few systematic monitoring systems for menopausal symptoms of patients on ET. We conducted a prospective, pilot study through the mobile platform-based monitoring solution which contains a questionnaire about menopausal symptoms to assess the feasibility of the solution. Methods We screened and collected data from HR-positive BC patients who underwent surgery at a single institution from May 2022, until recruiting a total of 20 patients. Patients scheduled for postoperative ET at age 50 or younger were included. Preoperatively confirmed metastatic BC patients were excluded. A total of 19 patients were enrolled, excluding one patient who self-discontinued medication. Menopause Rating Scale (MRS) surveys were periodically administered to the patients using a mobile platform-based solution to collect responses during first 3 months of ET. The primary endpoint of this study was the response rate of the patients, and the second endpoint was MRS scores and patient satisfaction. At the time of initial enrollment before the start of ET, MRS was collected using a paper questionnaire. The concordance rate of MRS response using a paper questionnaire and this solution was compared. We also conducted a user evaluation at the end of the third month of ET to determine satisfaction. The data collected from the solution were used by physicians to assist in patient care for clinical use. Results The median age of the cohort was 39 (range 29-47). Six patients were treated with Tamoxifen alone, Tamoxifen with LHRH analog in 12 patients, and AI with LHRH analog in 1 patient. There were 3 (15.8%) of pTis, 13 (68.4%) of pT1, and 3 (15.8%) of pT2, as well as 18 (94.7%) of pN0 and 1 (5.3%) patients of pN1. The total response rate of patients to the solution during the study period was 84.5%. Each symptom has different response rates and MRS scores, from 70.2% for sex-related symptoms to 95.4% for joint pain, and from 1.24 out of 4 for sleep disturbances to 0.45 out of 4 for vaginal dryness. The match rate between mobile and paper surveys was 90.0%. The overall satisfaction score for the solution of patients was 8.06 out of 10, with the highest score (8.79 out of 10) given in terms of using patients’ responses in outpatient appointments with the physician. Conclusion The analysis of MRS using this mobile solution in premenopausal BC patients undergoing postoperative ET is expected to be feasible for clinical use and should be analyzed in a large-scale study in the future. Citation Format: Dong Seung Shin, Jai Min Ryu, Byung Joo Chae, Jeong Eon Lee, Seok Won Kim, Seok Jin Nam, Jonghan Yu. The pilot study for a mobile-based monitoring solution to manage menopausal symptoms of premenopausal breast cancer patients with endocrine therapy [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 PO3-12-06.