Factor Receptor 2-negative Breast Research Articles

Quality-Assured Analysis of PIK3CA Mutations in Hormone Receptor–Positive/Human Epidermal Growth Factor Receptor 2–Negative Breast Cancer Tissue

In precision oncology, reliable testing of predictive molecular biomarkers is the prerequisite for optimal patient treatment. Interlaboratory comparisons are a crucial tool to verify diagnostic performance and reproducibility of one's approach. Here, we describe the design and results of the first recurrent, internationally performed PIK3CA Breast Cancer Tissue external quality assessment (EQA), which was organized by German Quality in Pathology (QuIP) GmbH and started in 2021. After the internal pretesting phase performed by the (lead) panel institutes, in both 2021 and 2022, each EQA test set comprised n=10 tissue samples of hormone receptor-positive, human epidermal growth factor receptor 2-negative invasive breast cancer (IBC) that had to be analyzed and reported by the participants. In 2021, the results were evaluated separately for German-speaking countries (part 1) and international laboratories (part 2). In 2022, the EQA was performed across the European Union. The EQA success rates were 84.6% (n=11/13), 88.6% (n=39/44), and 87.9% (n=29/33) for EQA 2021 part 1, EQA 2021 part 2, and EQA 2022, respectively. The most commonly used methodologies were next-generation sequencing and mutation-/allele-specific qualitative polymerase-chain-reaction-based assays. In summary, this recurrent PIK3CA EQA proved to be a suitable approach for quality assessment in predictive molecular biomarker testing, to obtain an international overview of methods used for PIK3CA mutation analysis and to identify the strengths and weaknesses of individual methods.

Abstract CT518: First-in-human dose-escalation study of the phosphatidylinositol 3-kinase α-selective inhibitor HS-10352 in advanced breast cancer

Abstract Background: PIK3CA mutation is particularly prevalent in hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) breast cancer. HS-10352 is a highly potent and selective small molecule inhibitor of phosphoinositide 3-kinase α. Preclinical studies have indicated the favorable safety and antitumor activity of HS-10352 in PIK3CA-mutated tumor models. Methods: A phase 1, open-label, dose-escalation study was conducted to assess the safety, tolerability, pharmacokinetics (PK) and preliminary anti-tumor activity, in patients (pts) with advanced HR+HER2- breast cancer for whom standard therapy was ineffective or unavailable. The rolling six dose-escalation scheme was used to determine the maximum tolerated dose (MTD). Tumor tissues were collected for retrospectively central determination of PIK3CA mutation status. Results: Eighteen pts were treated with HS-10352 orally once daily (2 mg n=3; 4 mg n=3; 6 mg n=6; 8 mg n=6). All patients were HR+HER2- female breast cancer with visceral metastases after a median number of 3 prior systemic therapies for advanced disease. The median treatment duration was 111.5 days (range: 13~388). Dose limiting toxicities occurred in 2 pts at 8 mg (2 Grade 3 hyperglycemia). The MTD was established as 6 mg. According to the CTCAE 5.0, the most common (≥ 30%) treatment-related adverse events (TRAEs) were hyperglycemia (88.9%, n=16), weight decreased (61.1%, n=11), insulin C-peptide increased and diarrhea (33.3% each, n=6). Grade 3-4 TRAEs were hyperglycemia (8 mg, n=2), weight decreased (6 mg, n=2), fatigue (8 mg, n=1), vision blurred (8 mg, n=1), hyperkalemia (8 mg, n=1) and hypocalcemia (8 mg, n=1). Hyperglycemia was generally manageable with oral anti-hyperglycemic medications (13/16). Treatment-related rash were mild (22.2%, grade 1: n=2; grade 2: n=2). The overall response rate (ORR) and disease control rate (DCR) for all patients (n=18) were 27.8% and 55.6% respectively. For 6 pts with PIK3CA mutation, ORR was 50.0% (confirmed partial response [PR] in 3 pts at 6 mg) and DCR was 100.0% (6 mg, n=4; 8 mg, n=2), and the 9-month progression-free survival (PFS) rate was 66.7% (95% CI: 28.9%~100.0%). Of 4 pts with PIK3CA mutation at potentially recommended phase 2 dose of 6 mg, three pts (75.0%) achieved confirmed PR and 1 patient (25.0%) had stable disease (PFS ≥ 7.4m). Plasma exposure of HS-10352 increased proportionally following single dose. The mean plasma half-life of HS-10352 was 11~15 hours. Conclusions: HS-10352 showed a manageable safety profile and favorable PK properties. The promising antitumor activity was observed in patients with HR+HER2- advanced breast cancer harboring PIK3CA mutation. Clinical trial information: NCT04631835. Citation Format: Quchang Ouyang, Ying Wang, Jian Zhang, Qiong Wu, Changan Sun, Hongying Wei, Xiaoling Qian, Xichun Hu. First-in-human dose-escalation study of the phosphatidylinositol 3-kinase α-selective inhibitor HS-10352 in advanced breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT518.

Phase 1 study of SGN-B7H4V, a novel, investigational vedotin antibody–drug conjugate directed to B7-H4, in patients with advanced solid tumors (SGNB7H4V-001, trial in progress).

TPS3155 Background: B7-H4, a B7 immune checkpoint ligand, is expressed at low levels in normal tissue and negatively regulates T-cell function by inhibiting T-cell proliferation and cytokine production. B7-H4 expression is elevated in solid tumors, including breast, ovarian, and endometrial cancers. Targeting B7-H4–expressing tumor cells may relieve B7-H4–mediated T-cell inhibition. SGN-B7H4V is a novel, investigational vedotin antibody–drug conjugate directed to B7-H4 with proposed mechanisms of action including monomethyl auristatin E (MMAE)-directed cytotoxicity, bystander effect, antibody-dependent cellular cytotoxicity, and antibody-dependent cellular phagocytosis. SGN-B7H4V elicited antitumor activity in cell line-derived xenograft models of triple-negative breast cancer (TNBC) and patient-derived xenograft models of TNBC and ovarian cancer (Gray et al 2021), providing a rationale to evaluate SGN-B7H4V in patients (pts) with advanced solid tumors. Methods: SGNB7H4V-001 (NCT05194072) is a phase 1, first-in-human, multicenter, open-label trial evaluating the safety, tolerability, pharmacokinetics (PK), and antitumor activity of SGN-B7H4V in pts with advanced solid tumors. This study includes 3 parts: dose escalation (Part A), dose and schedule optimization (Part B), and dose expansion in disease-specific cohorts and a biology cohort (Part C). Adult pts (≥18 years) with histologically/cytologically confirmed locally advanced unresectable or metastatic solid tumors including high-grade serous epithelial ovarian cancer, primary peritoneal cancer, fallopian tube cancer, human epidermal growth factor receptor 2-negative and hormone receptor-positive breast cancer, TNBC, endometrial carcinoma, squamous non-small cell lung cancer, cholangiocarcinoma, or gallbladder carcinoma, are eligible. Pts must have ECOG PS 0–1 and relapsed/refractory disease or be intolerant to standard-of-care therapies. Prior treatment with an MMAE-containing agent or a B7-H4–targeted agent is not permitted. Primary endpoints include the rate of adverse events, laboratory abnormalities, dose-limiting toxicities, and cumulative dose-level safety. Secondary endpoints are objective response rate (ORR), complete response rate, duration of objective response (DOR), progression-free survival (PFS), overall survival (OS), PK, and incidence of antidrug antibodies. Exploratory endpoints include pharmacodynamic (PD) analyses, PD and PK exposure measurements, B7-H4 characterization on malignant cells, and biomarker analyses. Safety and antitumor activity endpoints will be assessed using descriptive statistics. ORR will be analyzed by tumor type and dose. DOR, PFS, and OS will be estimated using the Kaplan–Meier method. Enrollment for Part A is ongoing in North America and is planned in Europe. Clinical trial information: NCT05194072.

A multicenter, open-label, phase 2 study of odetiglucan (IMPRIME PGG) and pembrolizumab in patients with metastatic breast cancer (mBCA) who have progressed through prior hormonal therapy.

TPS1115 Background: Hormone receptor (HR) positive/ human epidermal growth factor receptor 2-negative (Her2-) breast cancer is generally considered ‘immunologically cold’ in comparison to TNBC or Her2+ breast cancer. Keynote-028 results showed a modest ORR of 12% to anti-PD1 antibody, pembrolizumab (PEM) in previously treated HR+/ HER2-/programmed death ligand 1-positive (PD-L1-positive) advanced breast cancer patients (pts). With limited options available, there is significant unmet need to expand clinical benefit from ICI. Odetiglucan, a novel beta glucan, acts as a pathogen-associated molecular pattern (PAMP) that drives a cascade of immune activating events. It repolarizes the immunosuppressive microenvironment, activates the maturation of antigen presenting cells and significantly enhances efficacy of ICI therapy in preclinical tumor models. In a Ph2 trial (IMPRIME 1) of odetiglucan + PEM in 44 pts with heavily pretreated metastatic TNBC, an ORR=15.9%, DCR=54.5%, mDOR=12.7mo, mPFS=2.86 mo, 12 mo OS rate=57.6%, and mOS=16.4 mo were observed. Clinical benefit was particularly evident in a subset of pts, mTNBC “converters” (12/44 pts) who were originally diagnosed with ER/PR+ disease and progressed through endocrine therapies +/- CDK4/6 inhibitors. In these 12 pts, an ORR=50%, DCR=83%, mDOR=11.2, mPFS=5.6 mo, 12-mo OS rate=64.8%, and mOS=17.4 mo were observed. Methods: Odetiglucan + PEM is now being explored in pts with hormone-resistant metastatic breast cancer (MBC). This is a phase 2, Simon’s 2-Stage study of MBC pts who have progressed through prior hormonal therapy with >1 CDK4/6 inhibitor. Pts will receive odetiglucan 4 mg/kg/wk + PEM 200 mg Q3wk. Stage 1 will enroll 23 pts. If >4 pts have an objective response after 12 wks of treatment, the study will proceed to Stage 2 enrolling an additional 24 pts (N=47). Rejection of the null hypothesis requires >10 objective responses. Main eligibility criteria include: MBC having failed prior hormonal therapy with >1 CDK4/6 inhibitor, <2 chemotherapies, serum ABA ≥20 µg/mL, and no prior ICI exposure. Primary endpoint is ORR (RECIST v1.1); secondary endpoints are PFS, OS, DCR, DoR, and safety. Exploratory objectives assess impact of the treatment combination on immune activating events in peripheral blood and tumor biopsies, and correlate tumor microenvironmental changes with clinical benefit Select subpopulations may be explored. Point estimates with 95% confidence intervals (CIs) of ORR and DCR will be computed. Medians, first, and third quartiles with 95% CI will be estimated using Kaplan-Meier method for other secondary endpoints. Safety parameters will be summarized. The trial is sponsored by HiberCell, Inc. in collaboration with Merck & Co. ̃25 US sites will participate. Clinical trial information: NCT05159778.

Novel imaging marker for low- and mid-recurrence score patients at risk for recurrence.

e12565 Background: The 21-gene (Oncotype DX) recurrence score (RS) has been utilized as a prognostic assay in patients with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) breast cancer. The results stratify patients into low-, mid- and high-risk of disease recurrence. Patients with a low recurrence score tend to have lower recurrence rates and are less responsive to chemotherapy. On the other hand, patients with high-recurrence scores are more likely to respond to chemotherapy. While for patients at the high end of the RS spectrum it is apparent that chemotherapy carries benefit, distinguishing chemotherapy benefit for low- and mid-recurrence score (RS-low/-mid) patients is less clear. Methods: To address this, we used a novel 2-paramenter pharmacokinetic modeling framework that allows biosignatures to be extracted from dynamic contrast enhanced (DCE) magnetic resonance imaging (MRI) studies that contain 3-6 timepoints spaced 60-90 seconds apart. These parameters, referred to as P1 and P2, represent leakiness from vessels to the extravascular space and vice versa. Results: Using this model, we performed a study in a cohort of 111 breast cancer patients with 21-gene assay RS and DCE-MRIs available. P1 and P2 were extracted from patient standard clinical DCE-MRIs. We performed univariate (Kaplan-Meier) survival analyses to test the prognostic value of the parameters covariate in predicting recurrence free survival (RFS). A pre-specified value of the median P1 and P2 across the patient population was used for stratifying patients into “low” and “high” groups, representing patients with “low” or “high” vessel leakiness. We analyzed patients according to RS. Low P1 showed better outcomes in RS-low and RS-mid patients (n=88, p≤0.028; log-rank test). Patients with a high P1 had a 20.2% chance recurrence at six years. The same trend was observed when considering just RS-mid patients only (n=23, p≤0.058). No recurrences were observed in patients with low P1 in either the RS-low or RS-mid categories. Additionally, there were no recurrences in the high P1, RS-low/-mid category that received chemotherapy, suggesting that chemotherapy could be beneficial in this category of patients, although the trend was not statistically significant (n=10, p=0.46). Similar results were seen for P2. Conclusions: Overall, we demonstrate how our prognostic imaging marker can identify a subset of patients with low-/mid-recurrence scores that could benefit from chemotherapy. This new prognostic approach has the potential to optimize treatment and improve personalized care by providing clarity on the use of chemotherapy in low-/mid-recurrence score patients.[Table: see text]

Phase Ib/II study of BCL-2 inhibitor lisaftoclax (APG-2575) safety and tolerability when administered alone or combined with a cyclin-dependent kinase 4/6 (CDK4/6) inhibitor in patients with estrogen receptor-positive (ER+) breast cancer or advanced solid tumors.

TPS1122 Background: Various cancers evade apoptosis by overexpressing BCL-2 proteins. Investigational agent lisaftoclax (APG-2575) is a novel, potent, selective BCL-2 inhibitor, while palbociclib inhibits cyclin-dependent kinases (CDK) 4 and 6. In preclinical studies, palbociclib decreased proliferation of ER+ breast cancer cell lines by arresting them in the G1 cycle phase. Preclinical data demonstrate favorable, complementary effects of palbociclib when combined with a BCL-2 inhibitor and support this combination in patients with ER+/ human epidermal growth factor receptor 2-negative (HER2-) metastatic breast cancer. Methods: This global multicenter open-label dose escalation and dose expansion study is assessing the safety of lisaftoclax monotherapy in patients with histologically or cytologically confirmed advanced solid tumors that have progressed on standard therapy or when combined with CDK4/6 inhibitor palbociclib in physiologically postmenopausal women with ER+/ HER2- metastatic breast cancer that has progressed or relapsed after treatment with a CDK4/6 inhibitor. This trial consists of 2 parts: a phase Ib dose escalation phase using a standard 3+3 design to determine the maximum tolerated dose (MTD) of lisaftoclax as a single agent in patients with solid tumors, as well as both the MTD and recommended phase 2 (RP2D) dose of lisaftoclax when combined with palbociclib in women with ER+/ HER2- metastatic breast cancer. Phase II of this study is a signal-seeking expansion of lisaftoclax at RP2D when combined with palbociclib in women with ER+/HER2- metastatic breast cancer. This phase is being conducted using Simon’s Minimax two-stage design. The primary objective for phase II is to determine clinical benefit response, and secondary efficacy endpoints include overall response rate, duration of response, time to response, and progression-free survival. Lisaftoclax is being administered orally once daily in a 28-day cycle at the assigned dose. Clinical trial information: NCT04946864.

Phase I study combining pembrolizumab and aromatase inhibitor in patients with metastatic hormone receptor–positive breast cancer.

1053 Background: Aromatase inhibitor (AI) is standard of care for patients with hormone receptor positive (HR+) human epidermal growth factor receptor 2-negative (HER2-) metastatic breast cancer (MBC). The current phase I trial was designed to test the safety and efficacy of AI and the immune checkpoint inhibitor pembrolizumab (NCT 02648477). Methods: Key eligibility criteria were HR+ HER2- MBC per ASCO/CAP; RECIST 1.1 measurable disease; adequate organ function; and ECOG 0-1. Eligible patients received 200 mg pembrolizumab IV every 3 weeks plus AI until progression or unacceptable toxicity. Primary objectives were to evaluate the safety and efficacy of this combination. This study employed a 3-at-risk design with a lead-in at the standard dosing of both AI and pembrolizumab with a targeted accrual of 20 patients. Results: A total of 20 patients were accrued between March 2016 and April 2017. Median age was 62 (range 34-79), with 75% white, 15% Asian and 10% unknown. Median lines of therapy were 3 (0, 9). All but one patient received aromatase inhibitor and/or fulvestrant prior to enrollment. The combination was well tolerated, and the most common adverse events were grade 2 fatigue (35%), rash (15%), and hot flashes (10%). Grade 3 adverse events were elevated AST/ALT (5%), rash (5%), and lymphopenia (5%). Responses were 10% partial response and 15% stable disease, resulting in a clinical benefit rate (CBR) of 20% at 6 months. Median follow-up time was 40.1 months (range 31.3 – 46.8 months). Median progression free survival was 1.8 months (95% CI 1.6, 2.6) and median overall survival was 17.2 months (95% CI 9.4, NA). 14 tumor specimens had programmed death ligand 1–positive (PD-L1) by 22C3 testing, including 3 PD-L1-positive and 11 PD-L1 negative. No association between PD-L1 and response was found. Conclusions: The combination of pembrolizumab and AI is well tolerated in patients with HR+ HER2- MBC who were not pre-selected for PD-L1. There was minimal overall clinical activity observed beyond what was to be expected with AI alone in this group of patients. Clinical trial information: NCT 02648477.

Abstract P2-12-09: Correlation between pathologic complete response (pCR), event-free survival (EFS)/disease-free survival (DFS) and overall survival (OS) in neoadjuvant and/or adjuvant (NAdj/Adj) hormone receptor positive (HR+) and human epidermal growth factor receptor-2 negative (HER2-) breast cancer (BC)

Abstract Background OS, the “gold standard” endpoint in oncology studies, is challenging to measure in earlier stages of BC because of considerably long survival. Further, during extended patient follow-up, treatment effect on OS can become impacted by multiple factors such as non-malignant causes of death, treatment cross-over, and post-progression treatments, making it difficult to isolate the true treatment effect. As an alternative, surrogate endpoints (SE) such as DFS, EFS, and pCR can be used to ascertain meaningful benefit in true endpoint (TE). While studies have previously explored the association of such SEs with OS in different BC populations, there is a dearth in literature of studies reporting on correlation in the NAdj/Adj settings in the HR+/HER2- BC population. The aim of this study is to conduct a correlation analysis between various SE-TE pairs (DFS/EFS vs OS, pCR vs OS and pCR vs DFS/EFS) in this population, from data reported in studies identified from a systematic literature review (SLR). For each pair of endpoints, both absolute and relative treatment effects were evaluated. Methods An SLR was conducted in NAdj/Adj setting for HR+/HER2- BC to identify studies that reported any two of pCR, DFS/EFS and OS. The search was carried out using MEDLINE, Embase, Cochrane Library databases (2000 onward), four BC-related conference proceedings (2018-2020) and clinical trial registries. Relative treatment effect sizes were quantified in terms of HRs for DFS/EFS and OS, and odds ratios (ORs) for pCR. Absolute treatment effects were analyzed in terms of survival probability of EFS/DFS and OS at landmark time points and pCR rates. A weighted least squares regression analysis was carried out to determine the strength of association between the various TE-SE pairs. The regression analysis was carried out on log scale for relative treatment effects and on linear scale for absolute treatment effects. Pearson correlation coefficient (r) was used to quantify the strength of association; coefficient of determination (R2) was also reported to evaluate goodness-of-fit. Sensitivity analyses were performed by considering linear scale (for relative outcomes only), using inverse of variance as weights, and by removing outliers. Results A total of 135 publications were identified in the SLR. Regression analysis showed that there is a statistically significant positive association (r= 0.91; 95%CI, 0.83-0.96, p <0.0001) between log(HROS) and log (HRDFS/EFS), with R2 = 0.83. The correlation between log (HRDFS/EFS) and log(ORpCR) was not strong (r= 0.24; 95% CI, -0.63-0.84; p, 0.603). Correlation of ORpCR with HROS was not conducted due to inadequate data points (n=3). For the absolute outcomes, landmark DFS/EFS at 1 year and 2 years were each found to be moderately correlated with OS at 4 and 5 years. The correlation between pCR rate and landmark DFS/EFS and OS was not strong. The association between the pairs of the endpoints was consistent across all the sensitivity analyses. Conclusions Results of this regression analysis suggest that relative treatment effect on DFS/EFS is strongly associated with relative treatment effect on OS in HR+HER2- BC and could be used as a surrogate for OS. Correlation analysis for HR(DFS/EFS) vs. HR(OS) and OR(pCR) vs. HR(DFS/EFS)Model# studies# observationsPearson coefficient, r (95% CI)p-valueCoefficient of determination, R2 (95% CI)Slope (95% CI)P-valueHRDFS/EFS vs. HROS24320.91 (0.83-0.96)<0.00010.83 (0.69-0.89)0.99 (0.83-1.16)<.0001ORpCR vs. HRDFS/EFS570.24 (-0.63-0.84)0.60.06 (0-0.47)0.23 (-0.86-1.31)0.6099 Citation Format: Anagha Gogate, Inkyu Kim, Sandip Ranjan, Amit Kumar, Eros Papademetriou, Hitesh Bhandari, Ravi Potluri. Correlation between pathologic complete response (pCR), event-free survival (EFS)/disease-free survival (DFS) and overall survival (OS) in neoadjuvant and/or adjuvant (NAdj/Adj) hormone receptor positive (HR+) and human epidermal growth factor receptor-2 negative (HER2-) breast cancer (BC) [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 P2-12-09.

Abstract P3-12-15: Clinical characteristics, treatment patterns, and survival outcomes in women with early triple-negative (TN) or hormone receptor-positive/human epidermal growth factor receptor-2 negative (HR+/HER2−) breast cancer (BC) in the real-world (RW) setting

Abstract P3-12-15: Clinical characteristics, treatment patterns, and survival outcomes in women with early triple-negative (TN) or hormone receptor-positive/human epidermal growth factor receptor-2 negative (HR+/HER2−) breast cancer (BC) in the real-world (RW) setting

Abstract P3-09-04: Genomic landscape of HER2-negative advanced or metastatic breast cancer with PIK3CA gain-of-function mutations

Abstract Background: Alpelisib and fulvestrant are used as a combination treatment option for postmenopausal PIK3CA-mutated, hormone receptor positive (HR+), human epidermal growth factor receptor 2-negative (HER2-), advanced or metastatic breast cancer (a/mBC) patients. However, despite the presence of activating mutations in PIK3CA, the majority of patients do not derive benefit, or ultimately progress while on alpelisib therapy. Here, we investigate the genomic landscape of PIK3CA-mutated, HER2- a/mBC using next-generation sequencing (NGS) to provide insight into possible mechanisms of therapeutic resistance to alpelisib/fulvestrant and to identify potential targetable pathways. Methods: We utilized the Tempus LENS platform to retrospectively analyze de-identified NGS data from 2,918 a/mBC patients with formalin-fixed, paraffin-embedded tumor biopsies sequenced using the Tempus|xT solid tumor assay (DNA-seq of 595-648 genes at 500x coverage; full transcriptome RNA-seq). Mutations identified included germline and/or somatic single nucleotide variants, insertions/deletions and copy number variations (gains defined as ≥8 copies). We used curated clinical data to determine HER2 and hormone receptor (ER/PR) status. Results: Among 2,918 a/mBC patients, we identified somatic mutations in PIK3CA in 782 (26.8%). Within these tumors, 629 (80.4%) had one of the 11 mutations currently included in the alpelisib companion diagnostic, and we focused on this population (here defined as mut-PIK3CA). Of these 629, 546 (86.8%) were HER2-, with 176 (32.3%) and 370 (67.7%) derived from primary and metastatic tumors, respectively. Cases were further classified as HR+ (defined as ER+ or PR+) or triple negative (TNBC). While the majority of mutPIK3CA samples were identified in HR+ disease, 10% of the cases occurred in TNBC. Within the mutPIK3CA cohort, tumor mutational burden high (TMB-H; defined as ≥10 mutations/MB) was detected in 11.5% of samples, while microsatellite instability high (MSI-H) was detected in 0.5%. MSI-H was detected at a higher frequency in TNBC compared to HR+. Overall, the most commonly co-mutated genes among mutPIK3CA, HER2- samples were TP53 (34.6%), CDH1 (21.6%), ESR1 (12.3%), KMT2C (11%), MAP3K1 (9.5%), ARID1A (8.1%), PTEN (6.8%), GATA3 (6.6%), NF1 (5.9%), and TBX3 (5.9%) among others (Table 1); some of these genes have previously been implicated in resistance to endocrine therapy or PI3K inhibitor. In addition, in HR+ disease, metastatic samples had a higher frequency of mutations in genes implicated in endocrine resistance, such as ESR1 (18.7% vs 1.9%), ERBB2 (3.3% vs 2.6%), NF1 (6.8% vs 2.6%), compared to primary tumors. We also identified copy number gains (CNG) in several cell cycle genes, including: CCND1 (15.2%), CDK4 (2.7%), and AURKA (2.6%) (Table 1). Finally, further analyses at the transcript-level are the subject of on-going research. Conclusions: Our study highlights that there is substantial genomic heterogeneity among mutPIK3CA, HER2- a/mBCs. Across a series of comparisons between primary and metastatic samples, as well as HR+ and TNBC subtypes, we identified a number of co-mutations that occur alongside mutPIK3CA and which could be potentially exploited by targeted therapies. Future studies are needed to assess the prognostic/predictive role of these and other candidate gene alterations. Table 1. Genomic features of mutPIK3CA, HER2– a/mBCPrimaryMetastaticTotalAny PIK3CA Mutation1255527782mutPIK3CA2204425629HER2– (n=176)HER2– (n=370)546HR+ HER2– 154 (88%)TNBC 22 (12%)HR+ HER2– 337 (91%)TNBC 33 (9%)TMB-H16 (10.3%)2 (9.1%)41 (12%)4 (12%)63 (11.5%)MSI-H1 (0.6%)1 (4.5%)0 (0%)1 (3.0%)3 (0.5%)Co-mutations (mutPIK3CA): n (%)TP5347 (30.5%)14 (63.6%)101 (30%)27 (81.8%)189 (34.6%)CDH137 (24%)1 (4.5%)75 (22.3%)5 (15.2%)118 (21.6%)KMT2C17 (11%)1 (4.5%)40 (11.9%)2 (6.1%)60 (11%)MAP3K117 (11%)1 (4.5%)31 (9.2%)1 (3%)50 (9.2%)ARID1A15 (9.7%)0 (0%)26 (7.7%)2 (6.1%)43(7.9%)PTEN12 (7.8%)1 (4.5%)21 (6.2%)3 (9.1%)37 (6.8%)GATA311 (7.1%)0 (0%)23 (6.8%)2 (6.1%)35 (6.6%)TBX311 (7.1%)1 (4.5%)19 (5.6%)1 (3%)32 (5.9%)NCOR12 (1.3%)1 (4.5%)18 (5.3%)0 (0%)21 (3.8%)FOXA17 (4.5%)2 (9.1%)10 (3%)1 (3%)20 (3.7%)MAP2K41 (0.6%)1 (4.5%)12 (3.6%)1 (3%)15 (2.7%)ESR13 (1.9%)0 (0%)63 (18.7%)1 (3%)67 (12.3%)PIK3R13 (1.9%)0 (0%)4 (1.2%)0 (0%)7 (1.3%)AKT11 (0.6%)0 (0%)1 (0.6%)0 (0%)2 (0.4%)RB15 (3.2%)1 (4.5%)8 (2.4%)1 (3%)15 (2.7%)NF14 (2.6%)3 (13.6%)23 (6.8%)2 (6.1%)32 (5.9%)ERBB24 (2.6%)4 (18.2%)11 (3.3%)2 (6.1%)21 (3.8%)CCND1 CNG22 (14%)0 (0%)61 (18%)0 (0%)83 (15.2%)AURKA CNG3 (1.9%)0 (0%)11 (3.3%)0 (0%)14 (2.6%)CDK4 CNG5 (3.2%)1 (4.5%)7 (2.1%)1 (3.0%)14 (2.6%)1any somatic variant detected in PIK3CA2somatic PIK3CA mutations among the 11 currently included in the alpelisib companion diagnostic (C420R, E542K, E545A, E545D, E545G, E545K, Q546E, Q546R, H1047L, H1047R, and H1047Y) Citation Format: Jing Xi, Kathleen Harnden, Jingqin Luo, Greg S. Call, Elizabeth Mauer, Karyn Ronski, Cynthia X. Ma, Neil Vasan. Genomic landscape of HER2-negative advanced or metastatic breast cancer with PIK3CA gain-of-function mutations [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 P3-09-04.

Abstract ES10-3: IO beyond TNBC

Abstract Hormone receptor-positive breast cancer is not considered an immunogenic tumor, since characterized by lower level of programmed death-ligand 1 (PD-L1) expression and tumor infiltrating lymphocytes. Despite being a cold tumor some studies are addressing the question on potential role of immune-checkpoint inhibitors in the adjuvant or metastatic setting. The phase II Checkmate7A8 trial (NCT04075604) is investigating the combination of nivolumab, anastrozole, and palbociclib versus anastrozole with palbociclib as neoadjuvant therapy for postmenopausal women with luminal BC. The phase II ImmunoADAPT trial (NCT03573648) is studying the combination of tamoxifen, palbociclib, and avelumab versus tamoxifen with avelumab for patients with early-stage luminal BC, expecting to show an improvement in the radiological complete response rates assessed after four cycles of treatment. A phase I safety study is also investigating the combination of durvalumab, abemaciclib, and anastrozole in a similar population (NCT04088032). The Phase 3 CA209-7FL trial is a randomized, multicenter, placebo-controlled phase 3 study of nivolumab versus placebo in combination with neoadjuvant chemotherapy and adjuvant endocrine therapy in patients with high-risk, estrogen receptor-positive (ER+), human epidermal growth factor receptor 2-negative (HER2-) primary breast cancer. In the HER2 positive metastatic breast cancer the combination of pembrolizumab and trastuzumab administered upon progression on a trastuzumab-based regimen was investigated in the PANACEA study, which reported a response rate of 15%, restricted to PD-L1 positive tumors with a PFS benefit in the PD-L1 population. In the KATE2 trial, the addition of atezolizumab to trastuzumab emtansine in patients previously treated with trastuzumab demonstrated no significant benefit in PFS, although numerically higher PFS and response rates were observed in the PD-L1-positive population. A subsequent underpowered analysis (due to the small number of events) of the same trial suggested a possible OS benefit for patients with PD-L1-positive tumors. The combination of trastuzumab, pertuzumab, taxane, and atezolizumab is under investigation in the first-line setting (NCT03199885). The phase III IMpassion050 (NCT03726879) trial compares atezolizumab or placebo combined with neoadjuvant chemotherapy and dual anti-HER2 blockade for early-stage HER2-positive BC. This trial includes patients with PD-L1-positive and PD-L1-negative tumors and is considering pCR rates in the PD-L1-positive and ITT population as primary endpoints. In patients who do not achieve a pCR, TDM-1 is added in the adjuvant phase. The addition of atezolizumab to an anthracycline-free regimen of neoadjuvant chemotherapy and dual anti-HER2 blockade is the objective of the phase III APTneo trial (NCT035955592). In my presentation I will cover biological rational for IO studies beyond triple negative breast cancer in the attempt to provide an ideal immunogram for this population of patients. Citation Format: G Curigliano. IO beyond TNBC [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 ES10-3.

Abstract P3-14-11: Mammaprint and Blueprint identify genomic differences in HR+ HER2- breast cancers from young Black and White women

Abstract Introduction: Hormone receptor positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) breast cancer, the most common immunohistochemical subtype, remains the dominant contributor to annual breast cancer deaths worldwide across all racial and ethnic groups. Black women are 41% more likely to die from breast cancer compared to White women, predominantly among women diagnosed ≤ 50 years of age. Yet, Black women remain underrepresented in clinical trials and population-based studies. Thus, it is critical to better characterize tumor molecular features from young Black women to identify factors contributing to the existing racial survival disparity. In the current study, we compared risk of distant recurrence signature, MammaPrint (MP), molecular subtyping signature, BluePrint (BP), and whole transcriptome differences between young Black women with HR+ HER2- breast cancer compared to matched White controls. Methods: This study included 156 Black women aged ≤ 50 with stage I-III, HR+ HER2- breast cancer of whom, 68 were recruited from 2009-2014 as part of the BEST study (5R01CA204819-04) with follow-up data available (median 114.5 months). The remaining 88 Black women were enrolled in the ongoing FLEX Study (NCT03053193) from 2017. White women (n=156) were randomly selected from FLEX and matched by age, tumor stage, and receptor status. Tumors were classified through MP as Low Risk (MP-LR) versus High Risk (MP-HR), with MP-HR further stratified into HR1 and HR2; HR2 tumors exhibit superior chemosensitivity as demonstrated in a prior large clinical trial of breast cancer patients (ISPY2). All women had MP and BP to classify tumors as Luminal A (MP-LR), Luminal B (MP-HR), HER2, or Basal, and full transcriptomic analyses. Differential gene expression analysis was performed with R package ‘limma’ to compare Black and White women and further compare within each molecular subtype. Differentially expressed genes (DEGs) with a false discovery rate <0.05 were significant. Results: Of 312 young women with localized, HR+ HER2- breast cancer, high grade tumors were more frequent among Black compared to White women (34.6% vs 25.6%; p=0.08). MP-HR tumors were significantly more frequent among Black compared to White women (67.3% vs. 50.0%; p=0.002). Among MP-HR tumors, more HR2 tumors were seen in Black (25.6%) compared to White women (14.1%). Among women with MP-HR tumors and known treatment information, most Black women (94.3%) and all White women received chemotherapy. There were more Luminal B tumors in Black compared to White women (51.9% vs. 41.7%; p=0.07). BP reclassified a larger proportion of ER+ tumors as Basal in Black compared to White women (14.1% vs. 8.3%). Of 68 Black women with available survival data, 7 had death and/or distant recurrence events, of whom 6 (85.7%) had MP-HR tumors (4 Luminal B, 1 HER2, and 1 Basal) and 1 had MP-LR Luminal A tumor. Compared to White women, Black women with: 1) Luminal B tumors had 192 DEGs with upregulation of suspected poor prognosis genes, PSPH and IGHG1; 2) Luminal A tumors had upregulation of PSPH; and 3) Basal tumors had downregulation of POTEH. Conclusion: Among young women with localized HR+ HER2- breast cancer, MP and BP molecular signatures more robustly identified racial disparities in risk and subtype distribution beyond that identified through clinical factors adjusted for age and tumor characteristics. The transcriptomic differences among Black compared to White women across all BP subtypes provide novel insights about tumor biological differences. These findings have tremendous translational potential to identify etiologic underpinnings of racial survival disparities which may guide therapeutic strategies to improve outcomes. Citation Format: Sonya Reid, Tuya Pal, Ingrid A. Mayer, Xiao-Ou Shu, Ann L. Tezak, Kent Hoskins, Dipali Sharma, Patricia Robinson, Jennifer Wei, Jake Ruby, Shiyu Wang, Josien Haan, Andrea Menicucci, William Audeh, FLEX Investigators Group. Mammaprint and Blueprint identify genomic differences in HR+ HER2- breast cancers from young Black and White women [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 P3-14-11.

Abstract P1-16-06: In real world, a high percentage of premenopausal patients with hormone receptor-positive, HER2-negative metastatic breast cancer receive chemotherapy as first-line treatment: A study of the National Cancer Center, China

Abstract Background: In this study, we aimed to observe initial palliative treatment choices and clinical outcomes for premenopausal hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) metastatic breast cancer patients (MBC) in the Chinese population in real life.Methods: The China National Cancer Center database was used to identify 2194 MBC patients diagnosed between 2004 to 2015. Premenopausal patients with HR+ HER2- MBC were included. Clinicopathological features, initial palliative treatment choices and survival information were extracted. First-line progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan–Meier method and compared using the log-rank test. Prognostic factors associated with OS were analyzed using Cox regression model with 95% confidence interval (95%C.I.).Results: A total of 451 premenopausal patients meeting study criteria were identified. Median age was 44 years. The number of patients receiving chemotherapy alone, endocrine therapy and chemotherapy followed by endocrine therapy as initial palliative treatment strategy were 222(49.2%), 80 (17.7%), and 149 (33.0%), respectively. Patients receiving initial chemotherapy were more likely to be luminal B subtype, had more de novo stage IV disease than recurrent disease and had more liver metastasis, compared with patients receiving initial endocrine therapy. Both PFS and OS were significantly longer for chemotherapy-endocrine therapy group (median PFS 18.9 months and OS 75.0 months), than for endocrine therapy group (median PFS 11.7 months and OS 53.5 months). Chemotherapy alone group presented with worst survival outcomes (median PFS 7.1 months and OS 43.9 months). However, in multivariate analysis, none of the three treatment strategies were independently associated with PFS or OS.Conclusions: In real world, a high percentage of premenopausal patients with HR+ HER2- disease received chemotherapy as initial palliative treatment in China, which was not associated with worsened survival. This unexpected guideline non-adherence reflects the unmet need of establishing treatment guidelines specifically for premenopausal patients in the Chinese population. Further studies with larger sample size across China are needed to explore the relationship between this guideline non-adherence and clinical outcomes. Citation Format: Yiqun Li, Hongnan Mo, Xiuwen Guan, Shaoyan Lin, Zijing Wang, Yimeng Chen, Shanshan Chen, Qiao Li, Ruigang Cai, Jiayu Wang, Yang Luo, Ying Fan, Peng Yuan, Pin Zhang, Qing Li, Fei Ma, Binghe Xu. In real world, a high percentage of premenopausal patients with hormone receptor-positive, HER2-negative metastatic breast cancer receive chemotherapy as first-line treatment: A study of the National Cancer Center, China [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P1-16-06.

A nomogram for predicting probability of low risk of MammaPrint results in women with clinically high-risk breast cancer

We aimed to develop a prediction MammaPrint (MMP) genomic risk assessment nomogram model for hormone-receptor positive (HR+) and human epidermal growth factor receptor-2 negative (HER2–) breast cancer and minimal axillary burden (N0-1) tumors using clinicopathological factors of patients who underwent an MMP test for decision making regarding adjuvant chemotherapy. A total of 409 T1-3 N0-1 M0 HR + and HER2– breast cancer patients whose MMP genomic risk results and clinicopathological factors were available from 2017 to 2020 were analyzed. With randomly selected 306 patients, we developed a nomogram for predicting a low-risk subgroup of MMP results and externally validated with remaining patients (n = 103). Multivariate analysis revealed that the age at diagnosis, progesterone receptor (PR) score, nuclear grade, and Ki-67 were significantly associated with MMP risk results. We developed an MMP low-risk predictive nomogram. With a cut off value at 5% and 95% probability of low-risk MMP, the nomogram accurately predicted the results with 100% positive predictive value (PPV) and negative predictive value respectively. When applied to cut-off value at 35%, the specificity and PPV was 95% and 86% respectively. The area under the receiver operating characteristic curve was 0.82 (95% confidence interval [CI] 0.77 to 0.87). When applied to the validation group, the nomogram was accurate with an area under the curve of 0.77 (95% CI 0.68 to 0.86). Our nomogram, which incorporates four traditional prognostic factors, i.e., age, PR, nuclear grade, and Ki-67, could predict the probability of obtaining a low MMP risk in a cohort of high clinical risk patients. This nomogram can aid the prompt selection of patients who does not need additional MMP testing.

First-line treatment with a cyclin-dependent kinase 4/6 inhibitor combined with an aromatase inhibitor for hormone receptor-positive, human epidermal growth factor receptor-2 negative metastatic breast cancer: Population-based outcomes for patients treated in Alberta, Canada.

e13020 Background: Cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) in combination with an aromatase inhibitor (AI) has emerged as the standard first line treatment in patients with hormone receptor positive, human epidermal growth factor receptor-2 (HER-2) negative metastatic breast cancer (MBC). In this analysis, we describe population-based outcomes for first-line treatment with a CDK4/6i combined with an AI. Methods: All patients who were prescribed CDK4/6i + AI from January 2016 through June 2019 in a large Canadian province were included. Descriptive statistics were used to summarize patient demographics, tumor and treatment characteristics. Survival distributions were estimated using the Kaplan-Meier method. Multivariate analysis (MVA) using a Cox proportional hazards model was constructed to examine associations between potentially prognostic clinical variables and progression free survival (PFS). Results: A total of 316 patients were included. Median age was 61 years (interquartile range, 53-70 years), 82% were postmenopausal women, 39% had de novo MBC, and 48% had non-visceral disease. Palbociclib was prescribed in 94% of patients and the remaining patients received ribociclib. The CDK4/6i was dose-reduced upfront or during treatment in 47%. While 70% of the patients discontinued treatment due to progression, 30% stopped due to toxicity/patient preference/physician recommendation. With a median follow-up of 28.1 months, the median PFS was 37.9 months (95% CI, 26.7-NR). In the MVA, PR-negative tumour (HR, 2.37; 95% CI, 1.45-3.88; P = 0.001) and dose reduction of the CDK4/6i (HR, 1.51; 95% CI, 1.06-2.16; P = 0.022) predicted worse PFS. Median overall survival (OS) was not reached. The 30-month and 36-month OS rates were 74% and 68%, respectively. Of patients who progressed (n = 131), 89% received second-line treatment (chemotherapy in 46%, single agent hormonal therapy in 35%, hormonal therapy plus a targeted agent in 15%, and other in 4%). Median time to progression on second line chemotherapy was 9.0 (5.8-17.6) months and second line hormonal therapy +/- targeted agent was 4.0 (3.4-8.6) months (P = 0.012). Conclusions: The real-world outcomes of first-line use of CDK4/6i and AI are encouraging. PR negative tumors and dose reduction appear to be negative prognostic markers. CDK4/6i + AI as first-line treatment for HR-positive, HER2-negative MBC in Alberta is justified based on favorable PFS and early OS outcomes.

A phase 2 study of pamiparib in the treatment of patients with locally advanced or metastatic HER2-negative breast cancer with germline BRCA mutation.

1087 Background: Breast cancer is the most common cancer among women, with up to 37% of patients (pts) harboring germline BRCA1/2 mutations (g BRCA1/2m) that appear to be sensitive to poly (ADP-ribose) polymerase proteins 1 and 2 (PARP1/2) inhibition. Pamiparib is an orally administered selective PARP1/2 inhibitor that has the potential to cross the blood-brain barrier. This study evaluated the efficacy and safety of pamiparib in pts with locally advanced/metastatic human epidermal growth factor receptor 2-negative (HER2-) breast cancer, with deleterious or suspected deleterious g BRCA1/2m, who received ≤ 2 prior lines of chemotherapy. Methods: In this open-label, phase 2, multi-center study in China (NCT03575065), pts with locally advanced/metastatic HER2- breast cancer with deleterious or suspected deleterious g BRCA1/2m triple negative breast cancer (TNBC cohort) or hormone receptor-positive (HR+)/HER2- breast cancer (HR+ cohort) were enrolled. Pts received pamiparib 60 mg orally twice daily in 28-day cycles. The primary endpoint was objective response rate (ORR; RECIST v1.1) by independent review committee (IRC). Secondary endpoints included duration of response (DOR) and progression free survival (PFS) by IRC, overall survival (OS), safety and tolerability. Results: 88 pts were enrolled (median age 45.5 years), 76 pts (TNBC cohort n = 55; HR+ cohort n = 21) had measurable disease at baseline per IRC. 60 pts (68.2%) received 1 or 2 prior lines of chemotherapy; 42 pts (47.7%) were treated with platinum previously. Median follow-up was 13.77 months (TNBC cohort, 10.87 months; HR+ cohort, 18.45 months). In the TNBC cohort: confirmed ORR was 38.2% (95% CI: 25.4–52.3); median DOR (mDOR) was 6.97 months (95% CI: 3.94–not estimable[NE]); median PFS (mPFS) was 5.49 months (95% CI: 3.65–7.33); median OS (mOS) was 17.08 months (95% CI:13.70–NE). In the HR+ cohort: confirmed ORR was 61.9% (95% CI: 38.4–81.9); mDOR was 7.49 months (95% CI: 5.55–14.75); mPFS was 9.20 months (95% CI: 7.39–11.93); mOS was not reached (NR; 95% CI 18.10–NE). ≥ Grade 3 treatment emergent adverse events (TEAEs) occurred in 54 pts (61.4%); anemia was the most common TEAE, occurring in 77 pts (87.5%). Dose reduction due to TEAEs occurred for 57 pts (64.8%); discontinuations due to TEAEs occurred for 2 pts (2.3%). Conclusions: Pamiparib showed a promising response in pts with locally advanced/metastatic HER2- breast cancer with a g BRCA1/2m. The safety profile of pamiparib was considered acceptable and was generally consistent with therapies in the same class. Clinical trial information: NCT03575065 .[Table: see text]

Impact of clinical targeted sequencing on endocrine responsiveness in estrogen receptor-positive, HER2-negative metastatic breast cancer

Clinical targeted sequencing allows for the selection of patients expected to have a better treatment response, and reveals mechanisms of resistance to molecular targeted therapies based on actionable gene mutations. We underwent comprehensive genomic testing with either our original in-house CLHURC system or with OncoPrime. Samples from 24 patients with estrogen receptor-positive, human epidermal growth factor receptor 2-negative metastatic breast cancer underwent targeted sequencing between 2016 and 2018. Germline and somatic gene alterations and patients’ prognosis were retrospectively analyzed according to the response to endocrine therapy. All of the patients had one or more germline and/or somatic gene alterations. Four patients with primary or secondary endocrine-resistant breast cancer harbored germline pathogenic variants of BRCA1, BRCA2, or PTEN. Among somatic gene alterations, TP53, PIK3CA, AKT1, ESR1, and MYC were the most frequently mutated genes. TP53 gene mutation was more frequently observed in patients with primary endocrine resistance compared to those with secondary endocrine resistance or endocrine-responsive breast cancer. Recurrent breast cancer patients carrying TP53-mutant tumors had significantly worse overall survival compared to those with TP53-wild type tumors. Our 160-gene cancer panel will be useful to identify clinically actionable gene alterations in breast cancer in clinical practice.

Abstract OT-09-11: AMEERA-4, a phase 2 window study of SAR439859 vs letrozole in post-menopausal women with newly diagnosed estrogen receptor-positive (ER+)/human epidermal growth factor receptor 2-negative (HER2-) breast cancer

Abstract Background Endocrine therapy targeting estrogen receptor (ER) signaling is the standard of care for women with ER+ breast cancer. Selective ER degraders (SERDs) block ER signaling through dual competitive antagonism and receptor degradation. SAR439859, a potent, oral SERD, is in clinical development for ER+/HER- breast cancer. AMEERA-4 (NCT04191382; ACT16106) is a 14-day preoperative, non-therapeutic ‘window of opportunity’ trial to assess the direct effects of SAR439859 on tumor cell proliferation by evaluating the pharmacodynamic activity of SAR439859 in ER+/HER2- breast cancer. Methods This international, open-label, Phase 2 randomized study evaluates SAR439859 at two dose levels vs the aromatase inhibitor letrozole by assigning 126 preoperative patients 1:1:1 to receive SAR439859 400 mg/day, SAR439859 200 mg/day or letrozole 2.5 mg/day. SAR439859 dosing is based on an ongoing AMEERA-1 Phase 1/2 study (NCT03284957; TED14856) in metastatic breast cancer. Postmenopausal women with ER+/HER2- breast cancer indicated for immediate surgery (Stage I, Stage II or operable Stage III), Eastern Cooperative Oncology Group performance status 0-1, and Ki67 levels of ≥ 15% are eligible. Exclusion criteria include disorders potentially affecting absorption of SAR439859 or letrozole, and any prior therapy for breast cancer. Patients receive study treatment for 14 days, with the last dose given on the day before surgery. Paired tumor biopsies for assessment of biomarkers are performed at baseline and during surgery. The primary study endpoint is change in Ki67, a predictor of treatment benefit and long-term survival outcomes, after 14 days of treatment compared with baseline. Secondary endpoints include proportion of patients with ≥ 50% decrease in Ki67, ER expression to assess degradation, and safety. Pharmacokinetics of SAR439859, additional tumor markers, genomic mutation profile, Preoperative Endocrine Prognostic Index and pathological complete response will also be assessed. The study is currently recruiting. Funding: Sanofi. © 2020 American Society of Clinical Oncology, Inc. Reused with permission. This abstract was accepted and previously presented at the 2020 ASCO Annual Meeting. All rights reserved. Citation Format: Mario Campone, Christina Herold, Qiuyan Wang, Vasiliki Pelekanou, Sylvaine Cartot-Cotton, Bethany Ling. AMEERA-4, a phase 2 window study of SAR439859 vs letrozole in post-menopausal women with newly diagnosed estrogen receptor-positive (ER+)/human epidermal growth factor receptor 2-negative (HER2-) breast cancer [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr OT-09-11.

Abstract OT-09-09: AMEERA-3, a phase 2 trial of SAR439859 vs endocrine monotherapy in pre- and post-menopausal, estrogen receptor-positive (ER+)/human epidermal growth factor receptor 2-negative (her2−), locally advanced or metastatic breast cancer (BC) with prior exposure to hormonal therapies

Abstract Background Endocrine therapy (ET) targeting ER signaling is the mainstay of care for ER+ metastatic BC. There remains an unmet need in patients whose tumors become resistant to currently available ET. Selective ER degraders (SERDs) were developed to overcome resistance to existing ER-directed therapies by both competitively antagonizing and degrading ERs, while exploiting continued dependence of the tumor on ER signaling. SAR439859 is a potent SERD with robust preclinical ER degrading activity. In AMEERA-1, a Phase 1 dose escalation trial, SAR439859, had a favorable safety profile with no dose-limiting toxicities across all doses (20-600 mg once per day; QD). ER occupancy generally exceeded > 87% with plasma concentrations > 100 ng/mL. Overall response rate was 6.3% and the recommended Phase 2 monotherapy dose was 400 mg QD. Methods AMEERA-3 is an international, prospective, open-label, randomized Phase 2 study (NCT04059484; ACT16105) designed to assess safety and efficacy of SAR439859 in pts with ER+ (>1%)/HER2− metastatic or locally advanced BC progressing on ≥ 6 months of continuous ET (0-2 lines in the metastatic setting). Prior cyclin-dependent kinase (CDK) inhibitors are allowed. Exclusion criteria include: Eastern Cooperative Oncology Group performance status (ECOG PS) ≥ 2, life expectancy < 3 months, > 1 chemotherapy or targeted therapy in the metastatic setting, concomitant illness and factors potentially affecting SAR439859 absorption. Patients are randomized 1:1 to SAR439859 400 mg QD orally or physician’s choice of endocrine monotherapy (fulvestrant, tamoxifen, aromatase inhibitor). Patients receive 28-day cycles until unacceptable toxicity, progression, death, investigator decision, or patient request. Stratification factors include visceral metastases, prior CDK4/6 inhibitors, and ECOG PS. The primary endpoint is progression-free survival (Response Evaluation Criteria in Solid Tumors v1.1). Secondary endpoints include overall survival, response rate, duration of response, clinical benefit, pharmacokinetics, quality of life and safety. Target enrollment: n = 282; current enrollment: n = 9. Funding: Sanofi. © 2020 American Society of Clinical Oncology, Inc. Reused with permission. This abstract was accepted and previously presented at the 2020 ASCO Annual Meeting. All rights reserved. Citation Format: Sara Tolaney, Irfan Cicin, Rafael Betancourt, Arlene Chan, Diego Kaen, Peter Kaufman, Suzette Delaloge, Qianying Liu, Sylvaine Cartot-Cotton, Amele Amrate, Vasiliki Pelekanou, Katharine Cuff. AMEERA-3, a phase 2 trial of SAR439859 vs endocrine monotherapy in pre- and post-menopausal, estrogen receptor-positive (ER+)/human epidermal growth factor receptor 2-negative (her2−), locally advanced or metastatic breast cancer (BC) with prior exposure to hormonal therapies [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr OT-09-09.

Abstract PS13-29: Four cycles of docetaxel-cyclophosphamide versus anthracycline-taxane adjuvant chemotherapy in node negative, HER2-negative breast cancer: A real-world comparison

Abstract Background: It is unknown whether four cycles of docetaxel-cyclophosphamide (DC) is an appropriate adjuvant chemotherapy option in patients with lymph node negative (LNN) and human epidermal growth factor receptor-2 (HER2) negative breast cancer in place of widely adopted anthracycline-taxane (AT) regimens. In the Canadian province of Alberta, four cycles of DC has been used preferably in the last decade as a standard adjuvant chemotherapy regimen in LNN, HER2-negative disease. We aimed to retrospectively compare the survival outcomes of patients diagnosed with LNN, HER2-negative breast cancer in Alberta who were treated with four cycles of DC as compared to those treated with an AT regimens. Methods: We identified all patients who were diagnosed with LNN, HER2-negative breast cancer treated with adjuvant chemotherapy following surgical resection in Alberta from 2008 through 2012. We used propensity score methods to match each patient treated with an AT regimen to up to 4 patients treated with four cycles of DC on all known/potential clinicopathologic and treatment variables (Table).We compared the 10-year invasive disease free survival (iDFS), breast cancer specific-survival (BCSS) and overall survival (OS) between the two patient groups and assessed effect of type of adjuvant chemotherapy on iDFS, BCSS and OS using Cox regression analyses.Results: Of the 726 eligible patients, 657 (90.5%) were treated with four cycles of DC and 69 (9.5%) were treated with an AT regimen. Prior to matching, women who received four cycles of DC compared to those treated with an AT regimen, were more likely to be older, have higher Charlson co-morbidity score and mastectomy for definitive surgery, and in terms of disease: earlier stage, lower grade, and HR-positive status. Matching created a group of 202 women treated with four cycles of DC and eliminated differences in clinicopathologic and treatment features between the two patient groups (Table). Four cycles of DC compared to an AT regimen was not associated with reduced iDFS (HR = 0.91, 95% CI = 0.52 to 1.6, P = 0.75), BCSS (HR = 1.10, 95% CI = 0.51 to 2.37, P = 0.8), or OS (HR = 1.01, 95% CI = 0.48 to 2.17, P = 0.96).Conclusion: In this real-life comparison, four cycles of DC as compared with an AT regimen, yielded similar survival outcomes amongst patients with LNN, HER2-negative breast cancer. Table Baseline patient and tumour characteristics of 726 patients diagnosed with LNN, HER2-negative breast cancer by type of adjuvant chemotherapy. CharacteristicAT (n=69)DC (n=657)p value*Matched DC (n=202)†p value‡Age (years) Median465347 Mean (SD; range)45.8 (9.7; 25 - 69)52.6 (9.8; 23 - 78)<0.000146 (9.4; 23 - 69)0.8BMI Median25.327.526 Mean (SD; range)27.1 (6.7;17.5 - 62)28.5 (6.6;15.6 - 64)0.127.1 (5.8;17.3- 49.4)0.9Year of diagnosis [n (%)] 2007 - 200811 (15.9%)78 (11.9%)0.2426 (13%)0.8 2009 - 201022 (31.9%)275 (41.9%)68 (33.5%) 2011 - 201236 (52.2%)304 (46.3%)108 (53%)Charlson co-morbidity score [n (%)] Mean (SD, range)0.04 (0.26; 0 - 2)0.33 (0.67; 0 - 4)<0.00010.04 (0.27; 0-2)0.9 Score > 0 - no. of patients (%)2 (2.9%)151(23%)0.00057 (3.4%)0.8 067 (97.1%)506 (77%)195 (96.6%) 11 (1.45%)97 (14.8%)4 (2%) 21 (1.45%)44 (6.7%)3 (1.4%) 309 (1.4%) 401 (0.15%)Histology [n (%)] Ductal58 (84%)479 (72.9%)0.12165 (82%)0.8 Mixed Ductal-Lobular5 (7.25%)96 (14.6%)20 (9.9%) Others6 (8.7%)82 (12.5%)17 (8.4%)T-stage [n (%)] Stage I12 (17.4%)253 (38.5%)0.000537 (18.3%)0.9 Stage II57 (82.6%)404 (61.5%)165 (81.6%)Grade differentiation [n (%)] Well differentiated026 (4%)<0.00700.9 Moderately differentiated6 (8.7%)139 (21.2%)20 (9.9%) Poorly differentiated63 (91.3%)492 (74.9%)182 (90.1%)Hormone receptor status [n (%)] Positive33 (47.8%)468 (71.2%)<0.000195 (47%)0.9 Negative36 (52.2%)189 (28.8%)107 (52.9%)Definitive breast surgery [n (%)] Breast-conserving surgery30 (43.5%)390 (59.4%)<0.0190 (44.5%)0.9 Mastectomy39 (56.5%)267 (40.6%)112 (55.5%)Radiotherapy [n (%)]36 (52.2%)397 (60.4%)0.18103 (51%)0.9Time interval to first cycle of chemotherapy (months) Median2.732.82.71 Mean (SD; range)2.86 (0.77; 1.2- 4.8)3.25 (1.38; 0 - 15)0.52.82 (0.8; 0– 5.9)0.7 No. of patients (%) 0 months ≥ – < 3 months39 (56%)404 (61.5%)0.42122 (60%)0.6 3 months ≥ – < 6 months30 (43.4%)245 (37.2%)80 (40%) ≥ 6 months08 (1.2%)0Type of adjuvant chemotherapy [n (%)] DC×4657 (100%)202 (100%) FEC×3→D×363 (91.3%) AC×4→T×43 (4.35%)TAC×63 (4.35%) Citation Format: Malek Bassam Hannouf, Atul Batra, Sasha Lupichuka. Four cycles of docetaxel-cyclophosphamide versus anthracycline-taxane adjuvant chemotherapy in node negative, HER2-negative breast cancer: A real-world comparison [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS13-29.