Positive HER2 Negative Metastatic Breast Research Articles

240P Effect of dose intensity (DI) of palbociclib (PAB) and initial body weight dosage (BWD) on progression free survival (PFS): A real-world data analysis in patients with hormone-receptor (HR) positive HER2 negative metastatic breast cancer (MBC)

240P Effect of dose intensity (DI) of palbociclib (PAB) and initial body weight dosage (BWD) on progression free survival (PFS): A real-world data analysis in patients with hormone-receptor (HR) positive HER2 negative metastatic breast cancer (MBC)

Role of Intrinsic Subtype Analysis with PAM50 in Hormone Receptors Positive HER2 Negative Metastatic Breast Cancer: A Systematic Review.

Endocrine therapy (ET), associated with CDK 4/6 inhibitors, represents the first choice of treatment for HR+/HER2- metastatic breast cancer (mBC). Primary or secondary endocrine resistance could develop; however validated biomarkers capable of predicting such a conditions are not available. Several studies have shown that HR+/HER2- mBC comprises five intrinsic subtypes. The purpose of this systematic review was to analyze the potential correlations between intrinsic subtype, efficacy of treatment, and patient outcome. Five papers that analyzed the intrinsic subtype with PAM50 assay in patients (pts) with HR+/HER2- mBC treated with ET (alone or in combination) within seven phase III clinical trials (EGF30008, BOLERO-2, PALOMA-2,3, MONALEESA-2,3,7) were identified. Non-luminal subtypes are more frequent in endocrine-resistant pts and in metastatic sites (vs. primary tumors), have less benefit from ET, and worse prognosis. Among these, HER2-enriched subtypes are similar to HER2+ tumors and benefit from the addition of anti-HER2 agents (lapatinib) and, for less clear reasons, of ribociclib (unconfirmed data for palbociclib and everolimus). Basal-like subtypes are similar to triple-negative tumors, making them more sensitive to chemotherapy. The intrinsic subtype is also not static but can vary over time with the evolution of the disease. Currently, the intrinsic subtype does not play a decisive role in the choice of treatment in clinical practice, but has potential prognostic and predictive value that should be further investigated.

Abstract P5-13-06: Exploratory biomarker analysis in VERONICA, a phase 2 study of venetoclax + fulvestrant versus fulvestrant in patients with estrogen receptor (ER)-positive HER2-negative metastatic breast cancer (mBC)

Abstract BACKGROUND: Venetoclax (VEN) is a potent and selective inhibitor of the anti-apoptotic protein, BCL2. Preclinical studies have implicated the BCL2 family members, BCLXL and MCL1, in VEN resistance, and clinical studies in hematological malignancies have demonstrated subgroups with high ratios of BCL2/BCLXL and BCL2/MCL1 have the greatest VEN antitumor activity. The randomized phase 2 VERONICA study (NCT03584009) evaluated VEN in combination with fulvestrant (F) vs F alone in ER-positive, HER2-negative MBC pts who experienced disease recurrence/progression during or after a CDK4/6 inhibitor. Previously reported results from VERONICA (Lindeman et al. ASCO 2021) did not show an improved clinical benefit rate or progression-free survival (PFS) with VEN+F vs F alone. Here we present exploratory biomarker analyses of the expression of BCL2 family members and genomic alterations in circulating tumor DNA (ctDNA) and association with clinical outcomes from VEN+F vs F. METHODS: Tumor specimens were obtained during screening from 103 patients enrolled in the study, and expression levels of BCL2, BCLXL and MCL1 were analyzed by IHC. Baseline plasma-derived ctDNA was evaluated using the FoundationOne® Liquid assay. Expression of BCL2, BCLXL, MCL1 and mutations in ctDNA were correlated with PFS from VEN+F vs F based on the primary analysis (cutoff: Aug 5, 2020). RESULTS: In the overall population, protein levels of BCL2, BCLXL and MCL1 were similar between the VEN+F vs F arms. Patients whose tumors were BCL2 3+ trended towards having the greatest difference in median (m) PFS (3.9 months [mo] in VEN+F vs 1.7 mo in F; hazard ratio [HR] 0.38 [95% CI 0.09, 1.62]) albeit in a small sample size (n=13). Similarly, subgroup analysis suggested a trend for increasing mPFS and improved HR in VEN+F vs F alone in patients with the lowest BCLXL expression. mPFS in patients with a BCL2/BCLXL ratio ≥1 was 3.7 mo for VEN+F vs 1.8 mo for F (HR 0.67 [95% CI 0.3-1.49]) whereas patients with a BCL2/BCLXL ratio <1 had no difference in mPFS between the arms (2.0 mo in both arms, HR 1.21 [95% CI 0.7-2.1]). In the ctDNA-evaluable population, ESR1 (42.6%), TP53 (41.5%) and PIK3CA (35%) were the most prevalent genomic alterations observed and well-controlled between arms. PFS was similar between the ESR1 wildtype (wt) and mutant (mut) subgroups. TP53 mut status was a poor prognostic factor in both treatment arms. The PIK3CA wt subgroup had increased mPFS with VEN+F vs F alone (HR 0.66 [95% 0.38-1.17]) compared to PIK3CA mut (HR 1.59 [95% 0.74-3.34]). Patients with PIK3CA wt and BCL2 high tumors had the largest difference in mPFS between VEN+F (3.7 mo) vs F alone (1.9 mo) (HR 0.58 [95%CI 0.28-1.19]), compared to PIK3CA wt-BCL2 low tumors (2.4 vs 1.9 mo; HR 0.67 [95%CI 0.26-1.72]). CONCLUSION: Our data suggest that a high ratio of BCL2 to BCLXL conferred a trend towards a greater benefit to VEN+F compared to F alone, consistent with other clinical studies evaluating VEN. These analyses highlight the need to profile BCL2 and its family members to identify the VEN-sensitive subgroups, especially in indications where high expression of BCLXL or MCL1 may be observed. The ctDNA profile of VERONICA patients indicate a heavily pretreated patient population. The benefit observed in PIK3CA wt patients from VEN+F suggest increased dependence on BCL2 in this subgroup, while PIK3CA mut tumors likely rely on PI3K/AKT/mTOR survival programs or other BCL2 family members to evade apoptosis. Exploratory biomarker analyses are ongoing to further understand the VERONICA patient population. Citation Format: Geoffrey J. Lindeman, Tharu M. Fernando, Rebecca Bowen, Ching-Wei Chang, Rupal Desai, Kushagra Gupta, Aulde Fléchais, Timothy R. Wilson, Aditya Bardia. Exploratory biomarker analysis in VERONICA, a phase 2 study of venetoclax + fulvestrant versus fulvestrant in patients with estrogen receptor (ER)-positive HER2-negative metastatic breast cancer (mBC) [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 P5-13-06.

Multicentric real world evidence with palbociclib in hormone positive HER2 negative metastatic breast cancer in Indian population

The combination of cyclin dependent kinase 4/6 inhibitors with endocrine therapy is the standard therapy in hormone receptor positive HER-2 negative metastatic breast cancer (HR+/HER2− MBC). Several randomized trials have shown the benefits of this combination, however, real world evidence in the Indian patients is warranted. The present study reports the largest real world multicentric data from Indian population on the use of Palbociclib in HR+/HER2− MBC. A multicentric study on the HR+/HER2− MBC patients who received palbociclib with hormonal agent (Aromatase inhibitors/Fulvestrant) between February 2017 and May 2020 was conducted. Clinical and demographic information and survival data was retrieved from the Hospital medical records. Among a total of 188 patients, 57% patients were premenopausal and 17% patients had bone only disease. Altogether, 115 (61%) patients received palbociclib with Aromatase inhibitors in the first line whereas 73 (39%) patients received it in the second line with Fulvestrant. The median follow up period with advanced disease was 13 months. The median progression free survival in the first line and second line was 20.2 months and 12 months, respectively (p-value < 0.0001). The objective response rate was 80% and 47.9% in first and second lines, respectively. Dose interruptions/ discontinuation were done in 14.9% and 2.7% patients in the first and second lines, respectively. In terms of toxicity, 10% patients had grade 3–4 adverse events. The present real world data of the use of palbociclib in Indian population suggests similar effectiveness to previously published real world evidences and has been adapted as the standard of care in the first and second line treatment of HR+/HER2− MBC.

Endocrine Therapy Versus Chemotherapy as First Line Treatment in Metastatic Hormone Receptor Positive Breast Cancer

Introduction: The standard treatment of hormone receptor positive Her2 negative metastatic breast cancer is endocrine therapy with or without targeted therapy (e.g.CDK4/6inhibitors and mTOR inhibitors). Chemotherapy is indicated only in visceral crisis and the presence of visceral metastases is not indication for chemotherapy Aim of study The retrospective study aimed to characterize treatment and outcomes for patients with hormone receptor positive metastatic breast cancer in Alexandria clinical oncology department to review change in treatment trend during the last 10 years. Physician questionnaire to determine their preferences in choosing treatment. Methods Retrospective study using patient files of adult female diagnosed and treated at Clinical Oncology and Nuclear Medicine Department, Alexandria Main University Hospitals during the period from January 2010 to December 2019. Physician questionnaire was done by physician recruitment via online survey &amp; scientific meetings. Results: The study identified 611 women with hormone receptor positive metastatic breast cancer, median age was 50years, 48.9% were postmenopausal, 56.7% of hormone receptor positive, Her2 negative patients received chemotherapy as first line systemic treatment, 69.5% of these patients received chemotherapy as first line treatment in the first 5years. But, 48.8% of these patients received chemotherapy as first line in the last 5years and the study showed that median overall survival for all studied patients was 34 months. In contrast, the physician questionnaire showed that 75% of physicians prefer endocrinal therapy as first line treatment for hormone receptor positive, Her2 negative metastatic breast cancer. Conclusion: There is significant change in practice pattern in choosing the first line treatment between the first and last 5 years. Also, there is a discrepancy between practice pattern and physician preferences in choosing the first line systemic treatment for hormone receptor positive, Her2 negative metastatic breast cancer. The reason is the unavailability of most targeted agents (e.g; CDK4/6 inhibitors and mTOR inhibitors) and some hormonal agents such as fulvestrant.

The association of HER2 low expression with the efficacy of CDK4/6 inhibitor in hormone receptor positive HER2 negative metastatic breast cancer.

1052 Background: Markers for the efficacy of CDK4/6 inhibitor in estrogen receptor (ER) positive, HER2 negative advanced breast cancer are limited. The bidirectional crosstalks that exist between ER and HER2 pathways contribute to endocrine resistance. We investigated the association between low levels of HER2 expression and the clinical outcome of patients with ER+ HER2- metastatic breast cancer (MBC) treated with CDK4/6 inhibitors. Methods: We identified consecutive patients with ER+ HER2- MBC who received CDK4/6 inhibitor plus either letrozole or fulvestrant between Mar 2017 - Jun 2020 from an institutional cancer registry. HER2-low expression was defined as IHC score 1+, or 2+ with a negative ISH. Progression-free survival (PFS) was defined as the time from the initiation of CDK4/6 inhibitor to the date of radiological or clinical progression, or death. The relationship between HER2 expression levels and PFS was evaluated using log-rank test and multivariable Cox regression modelling. Results: 106 women with MBC were eligible for analysis. Median age at treatment was 58 (23.0-91.4). The majority received palbociclib (84%) while the rest received ribociclib. CDK4/6 inhibitor was used as first-line treatment in 50.9% of cases. Most tumors were of ductal histology (83%) and progesterone receptor (PgR) positive (84.9%), and 22.6% of the patients had bone-only disease. 77.3% of cases were considered HER2-low expressing. HER2-low expression was associated with a significantly shorter PFS compared with HER2 IHC 0 counterpart (median, 8.9 vs 18.8 months, p= 0.014). In multivariate analysis, HER-2 low expression remained significantly associated with an inferior PFS (HR 1.96, 95%CI 1.03-3.75, p= 0.041) after adjusting for the line of treatment, PgR status and disease extent (bone only vs extra-osseous disease). Conclusions: In patients with ER+ HER2- MBC treated with CDK4/6 inhibitors, HER2-low expression was associated with an inferior PFS, and may serve as a potential marker candidate for CDK4/6 inhibitor efficacy. As novel anti-HER2 antibody-drug conjugates demonstrated efficacy in HER2-low expressing MBC, coupled with the emerging evidence for the combination of CDK4/6 inhibitors with anti-HER2 agents, this HER2-low expression subgroup warrants prospective evaluations in future trials.

BPI20-022: Use of Cyclin Dependent Kinase 4/6 Inhibitors in Hormone Receptor Positive HER2 Negative Metastatic Breast Cancer. Experience in a Third Level Hospital in Mexico City

"BPI20-022: Use of Cyclin Dependent Kinase 4/6 Inhibitors in Hormone Receptor Positive HER2 Negative Metastatic Breast Cancer. Experience in a Third Level Hospital in Mexico City" published on 20 Mar 2020 by National Comprehensive Cancer Network.

Abstract P1-19-12: Patterns of treatment with everolimus and exemestane in hormone receptor positive HER2 negative metastatic breast cancer in the era of targeted therapy

Abstract Background: In 2012 the FDA approved everolimus and exemestane (EE) as second line therapy for patients who have progressed on letrozole or anastrozole, based on the BOLERO-2 trial which showed improvement in PFS with EE compared to exemestane alone (6.9 vs 2.8 months). Currently, aromatase inhibitors (AI), or fulvestrant (F), alone or in combination with a CDK4/6 inhibitor (CDK4/6i) are the most commonly used first line endocrine therapies for hormone receptor (HR) positive HER2 negative metastatic breast cancer (mBC). There is currently no clinical trial data regarding the efficacy of EE in patients previously treated with CDK4/6i. The goal of this project was to explore the treatment patterns of EE in this contemporary patient population, with particular interest in those who had received prior CDK4/6i plus AI/F, as first, second, or third-line treatment. Methods: The Flatiron Health electronic health record-derived nationwide database selected de-identified patients with HR positive HER2 negative mBC and the first (1L), second (2L), and third line (3L) treatments they received. Duration of treatment (DOT) is defined as time from the date of initiation of a line of treatment to the day prior to initiation of subsequent line of treatment; prolonged DOT is defined as duration ≥ 6 months. Medical non-cancer co-morbidities listed as defined by the Charlson Comorbidity Index were included. Median DOT was compared using t-test, unadjusted for patient and disease characteristics. Statistical analysis was performed using Python v3.7. Results: A total of 8457 HR positive HER2 negative patients diagnosed with mBC between 1/2011 and 1/2019 were identified. Of these, 726 patients received EE in 1L (N=127), 2L (N=326), or 3L (N=273). In this cohort, 72.3% of patients were diagnosed between 2011-2014, and 27.7% were diagnosed after 1/2015, and most (94.6%) were treated in the community setting. The majority were female (98.4%), Caucasian (75.1%), and had no co-morbidities (79%); the mean age was 64. A quarter of patients (25%) had de novo mBC. The median DOT for 1L EE was 7.6 months (95% CI 5.6, 9.6); 56.7% received 1L EE for ≥6 months. The median DOT for 2L EE was 9.1 months (95% CI 7.6,10.6) following 1L AI/F and 10.7 months (95% CI 8.5,12.9) following 1L AI/F plus CDK4/6i (p&amp;lt;0.02). Over half (52%) of patients received 2L EE for ≥6 months following 1L AI/F, and 32% received 2L EE for ≥6 months following 1L AI/F plus CDK4/6i (p&amp;lt;0.005). The median DOT for 3L EE was 5.6 months (95% CI 3.8, 7.3) following 2L AI/F 2L vs 4.1 months (95% CI 3.1, 5.0) following 2L AI/F plus CDK4/6i (p&amp;lt;0.01). 48.5% received 3L EE for ≥6 months following 2L AI/F vs 34.2% following 2L AI/F plus CDK4/6i (p=0.06). Conclusion: In a cohort of patients with HR positive HER2 negative mBC who received EE in the 2L or 3L, a significant percentage of patients derived clinical benefit (DOT&amp;gt;6 months) from EE, even after CDK4/6i therapy. Patients who received CDK4/6i 1L had longer unadjusted DOT of 2L EE compared to those who received 1L AI/F alone. NMedian DOT (mo), 95% CIProlonged DOT (%)1L EE1277.6 (95% CI 5.6, 9.6)56.7%1L AI/F→2L EE2009.1 (95% CI 7.6, 10.6)52.0%1L AI/F + CDK4/6i→2L EE5010.7 (95% CI 8.5, 12.9)32.0%2L AI/F→3L EE995.6 (95% CI 3.8, 7.3)48.5%2L AI/F + CDK4/6i→3L EE734.1 (95% CI 3.1, 5.0)34.2% Citation Format: Mariya Rozenblit, Lajos Pusztai, Kerin Adelson, Sarah Mougalian. Patterns of treatment with everolimus and exemestane in hormone receptor positive HER2 negative metastatic breast cancer in the era of targeted therapy [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P1-19-12.

NEW STRATEGY FOR DRUG TREATMENT OF LUMINAL HER2-NEGATIVE METASTATIC BREAST CANCER

The article deals with the new oral target drug Palbociclib and its place in estrogen-receptor therapy, a positive HER2-negative metastatic breast cancer. Until recently, the consistent endocrine therapy was the primary treatment for the patients of this subgroup, as it significantly improved clinical outcomes of the disease. However, in the vast majority of cases, the tumor demonstrated the acquired, and sometimes the original, hormone resistance, which sooner or later led to failure of treatment and to the progress of the disease. Discovery of the role of cycline- dependent kinases (CDK) in the activation of the tumor proliferation and the subsequent creation of the first inhibitor, CDK 4 and 6 types of Palbociclib, led to a fundamental change in the situation: The results of the clinical examination of the combinations of Palbociclib with Letrozole or Fulvestrantom showed doubling of the median survival rate without the disease progress compared to single hormonal therapy. This strategy called Therapy of Breakthroughs combines proven efficiency, good tolerability, maintains a high quality of life and should be used in patients with an al-positive HER2-negative metastatic breast cancer.

Phase 2 trial of trastuzumab and/or everolimus in hormone-resistant HER2-negative metastatic breast cancer.

576^ Background: Increased signaling through growth factor receptor pathways, including HER2, has been demonstrated to play a role in resistance to endocrine therapy. Efficacy of inhibiting HER2 and mTOR in HER2-negative, hormone-resistant breast cancer has been previously demonstrated. We evaluated the ability of inhibition of HER2 with trastuzumab (TRAST) and/or mTOR with everolimus (EVER) to reverse resistance to endocrine therapy in patients with hormone receptor (HR)-positive HER2-negative metastatic breast cancer (MBC). Methods: Eligibility included HR-positive, HER2-negative (IHC 1+ or 2+ and/or FISH negative) MBC on metastatic biopsy and documented progression within 6-months of starting an endocrine agent in the metastatic setting. Patients continued on the endocrine agent they had experienced disease progression on and were randomized to receive TRAST (8mg followed by 6mg every 3-weeks) or EVER 10mg daily. At disease progression the other agent (TRAST or EVER) was added. Biopsies of metastatic l...